Diamide compound and medicine containing the same

ABSTRACT

The present invention relates to diamide derivatives represented by the following general formula (1):  
                 
 
     wherein A is a phenyl group or the like, which may be substituted, B is —CH═CH—, —C≡C—, —(CH═CH) 2 —, —C≡C—CH═CH—, —CH═CH—C≡C—, phenylene or the like, and W is  
                 
 
     and medicines comprising such a compound. These compounds have an excellent inhibitory effect on the production of an IgE antibody and are hence useful as antiallergic agents and the like.

TECHNICAL FIELD

[0001] The present invention relates to novel diamide compounds andmedicines useful in preventing and treating allergic immunologicaldiseases, comprising such a compound as an active ingredient.

BACKGROUND ART

[0002] IgE, which is a kind of immunoglobulin (Ig), is anallergen-specific molecule produced by an IgE producing celldifferentiated from a B cell. This process is triggered by the contactof an immunocyte with an allergen in vivo.

[0003] IgE is produced in a target organ for an allergy and binds to areceptor on the surface of a mast cell, which is a central effector cellin an allergic reaction (sensitized state), or basophil. After thesensitization, allergic chemical mediators such as histamine,leukotrienes, prostaglandins and PAF, and injuring enzymes such astriptase are released from the mast cell stimulated by the reaction ofthe specific IgE and the allergen which invades in the living body, sothat immediate responses, such as vascular permeability acceleration,smooth muscle constriction, and vasodilation are elicited. Further,cytokines such as IL-4, which directly activate other immune systemcells, are also secreted from the stimulated mast cell. As a result,eosinophils, basophils and the like infiltrate into a tissue, and theallergic chemical mediators and tissue injuring proteins such as MBP,which are secreted by these inflammatory cells, induce a late response,so that the allergic symptom is lingered and taken seriously ill.

[0004] From this, IgE is considered a substance fundamentallyparticipating in the attack of an allergic immunological disease.

[0005] Therefore, several compounds having an inhibitory effect on theproduction of an IgE antibody have been found and reported to date witha view toward developing antiallergic agents [Pharmacology and Therapy,1994, 22(3), 1369; Japanese Patent Application Laid-Open No.106818/1989; Japanese Patent Publication No. 17506/1995; and JapanesePatent Application Laid-Open No. 92216/1996]. However, the object hasbeen not always sufficiently achieved under the circumstances.

[0006] Accordingly, it is an object of the present invention to find acompound having a strong inhibitory effect on the production of an IgEantibody so as to provide a medicine effective for allergicimmunological diseases, comprising this compound as an activeingredient.

DISCLOSURE OF THE INVENTION

[0007] With the foregoing circumstances in view, the present inventorshave carried out an extensive investigation. As a result, it has beenfound that novel diamide compounds represented by the general formula(1), which will be described subsequently, salts thereof, or hydrates orsolvates thereof have an excellent inhibitory effect on the productionof an IgE antibody and are useful for medicines such as antiallergicagents, thus leading to completion of the present invention.

[0008] According to the present invention, there is thus provided acompound represented by the following general formula (1):

[0009] wherein A is a phenyl, naphthyl, dihydronaphthyl, indenyl,pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl group which may besubstituted;

[0010] B is a group of —CH═CH—, —C≡C—, —(CH═CH)₂—, —CH═CH—C≡C— or—C≡C—CH═CH—, or a divalent residue of benzene, pyridine, pyrimidine orpyrazine; and

[0011] W is a formula

[0012] in which X is (Y¹, Y² and Y³ are

[0013] the same or different from one another and are independently ahydrogen atom, —COOR¹ (R¹ is a hydrogen atom or a lower alkyl group),—CON(R²)R³ (R² and R³ are the same or different from each other and areindependently a hydrogen atom, or a hydroxyl or lower alkyl group),—CH₂—N(R⁴)R⁵ (R⁴ and R⁵ are the same or different from each other andare independently a hydrogen atom or a lower alkyl group, or R⁴ and R⁵may form, together with the adjacent nitrogen atom, a heterocyclic ringwhich may further have an oxygen, nitrogen or sulfur atom), or —CH₂—S—R⁶(R⁶ is a lower alkyl, phenyl or pyridyl group), or Y¹ and Y² may coupleto each other to form an alkylene group which may be through an oxygen,a nitrogen or a sulfur, Z is a benzene or pyridine ring, and n is aninteger of 2 or 3, with the proviso that when B is a p-phenylene group,and W is a 1,4-piperazinyl group, A is not a phenyl group, and when B is—CH═CH—, A is not a phenyl group which may be substituted,

[0014] or a salt thereof, or a hydrate or solvate thereof.

[0015] According to the present invention, there is also provided amedicine comprising the above compound as an active ingredient.

[0016] According to the present invention, there is further provided amedicinal composition comprising the above compound and apharmaceutically acceptable carrier.

[0017] According to the present invention, there is still furtherprovided use of the above compound for a medicine.

[0018] According to the present invention, there is yet still furtherprovided a method of treating an allergic immunological disease, whichcomprises administering an effective amount of the above compound.

BEST MODE FOR CARRYING OUT THE INVENTION

[0019] The amide compounds according to the present invention arerepresented by the general formula (1). In these compounds, the loweralkyl groups include linear or branched alkyl groups having 1-8 carbonatoms. Specific examples thereof include methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyland octyl groups. Of these, those having 1-6 carbon atoms, for example,methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyland n-hexyl groups, are particularly preferred.

[0020] The lower alkoxy groups include linear or branched alkoxy groupshaving 1-8 carbon atoms. Specific examples thereof include methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy,tert-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy groups. Ofthese alkoxy groups, those having 1-6 carbon atoms are preferred.

[0021] The halogen atoms include fluorine, chlorine, bromine and iodineatoms.

[0022] In the formula (1), A is a phenyl, naphthyl, dihydronaphthyl,indenyl, pyridyl, indolyl, i-indolyl, quinolyl or i-quinolyl group.These groups may have 1-3 substituents. Here, examples of thesubstituents on these groups include a hydroxyl group, halogen atoms,lower alkyl groups which may be substituted by 1-3 halogen atoms, loweralkoxy groups, an amino group which may be substituted by one or twolower alkyl groups, and alkylthio groups.

[0023] Particularly preferable examples of A include tri-loweralkoxy-phenyl groups.

[0024] In B, examples of the substituent on the divalent residue ofbenzene, pyridine, pyrimidine or pyrazine include nitro, amino, loweralkyl and lower alkoxy groups, and halogen atoms.

[0025] More preferred as B is —CH═CH—, —C≡C—, —(CH═CH)₂—, —C≡C—CH═CH—,—CH═CH—C≡C—, or a divalent residue of benzene, pyridine, pyrimidine orpyrazine. Of these, —CH═CH—CH═CH—, —C≡C—CH═CH—, —CH═CH—C≡C— and abenzene residue (phenylene group) are particularly preferred.

[0026] In the general formula (1), preferable example of theheterocyclic ring which is formed by R⁴ and R⁵ together with theadjacent nitrogen atom include those having 3-10 carbon atoms. Specificexamples thereof include pyrrolidine, oxazole, isoxazole, thiazole,isothiazole, imidazole, imidazoline, imidazolidine, pyridine,piperidine, piperazine, morpholine and phthalimide. The alkylene groupformed by bonding Y¹ and Y² to each other preferably has 3-8 carbonatoms. Rings formed by the alkylene group which may be through anoxygen, a nitrogen or a sulfur include pyrrolidine, imidazolidine andpiperazine. More preferred as Y¹, Y² and Y³ are a hydrogen atom, andcarboxyl, aminomethyl, di-lower alkyl-amino and lower alkyl-aminomethylgroups, with a hydrogen atom, and carboxyl, aminomethyl, dimethylaminoand dimethylaminomethyl groups being particularly preferred.

[0027] Particularly preferred as W is piperazine or homopiperazine ringwhich may be substituted by a carboxyl, aminomethyl, di-loweralkyl-amino or di-lower alkyl-aminomethyl group, or

[0028] Incidentally, in the general formula (1), A is not a phenyl groupwhen B is a p-phenylene group, and W is a 1.4-piperazinyl group. A isnot a phenyl group which may be substituted when B is —CH—CH—.

[0029] The salts of the diamide compounds (1) may be any salts so far asthey are pharmaceutically acceptable salts. Examples thereof includemineral acid salts such as sulfates; organic acid salts such asmethanesulfonates, acetates, oxalates and citrates, and besides in thecase where the diamide compounds (1) are acidic compounds, alkali metalsalts such as sodium salts and potassium salts; alkaline earth metalsalts such as calcium salts and magnesium salts; and organic basic saltssuch as pyridine salts, picoline salts and triethylamine salts.

[0030] The diamide compounds (1) may be present in the form

[0031] The diamide compounds (1) can be prepared in accordance with, forexample, the following reaction formula:

A—B—COOH+H—Z—H →

[0032]

[0033] More specifically, the compounds (1) according to the presentinvention are obtained by the N-acylating reaction of a carboxylic acid(2) or a reactive derivative thereof with an amine (3).

[0034] The N-acylating reaction may be conducted by using anyN-acylating reaction known per se in the art. It is particularlypreferable to apply, for example, (a) a method in which the carboxylicacid (2) and the amine (3) are reacted in the presence of a base and/ora condensation agent in a solvent, or (b) a method in which a reactivederivative of the carboxylic acid (2) and the amine (3) are reacted in asolvent.

[0035] Examples of the solvents used in these reactions may includedimethylformamide, tetrahydrofuran, dioxane, acetonitrile, methylenechloride and dichloroethane. Examples of the base may include organicbases such as pyridine, triethylamine and diisopropylethylamine, andinorganic bases such as sodium carbonate and sodium hydrogencarbonate.Examples of usable condensation agents include1,3-dicyclohexylcarbodiimide,1-cyclohexyl-3-morpholinoethylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1,1′-carbonyldiimidazole,diethyl phosphorocyanidate, diphenylphosphoryl azide,bis(2-oxo-3-oxazolidinyl)phosphinic chloride and2-chloro-1-methylpyridinium iodide. Examples of usable derivatives ofthe carboxylic acid include acid halides such as acid chlorides, acidazides, symmetric acid anhydrides, mixed anhydrides with pivalic acid orthe like, and active esters such as cyanomethyl esters and p-nitrophenylesters.

[0036] In each of the method (a) and the method (b), the N-acylatingreaction is completed by reacting the carboxylic acid (2) or thereactive derivative thereof with the amine (3) at a reaction temperatureof 0 C. to 100° C. for 30 minutes to 30 hours. The isolation andpurification of the compound (1) from the reaction mixture may beconducted by using any methods known per se in the art, for example,filtration, extraction, washing, drying, concentration,recrystallization and various kinds of chromatography.

[0037] The compound (1) thus obtained may be converted into anacid-addition salt in a method known per se in the art.

[0038] The compound may also be converted into a solvate with a solventfor reaction, a solvent for recrystallization, or the like, inparticular, a hydrate.

[0039] Since the diamide compounds (1) according to the presentinvention have an excellent inhibitory effect on the production of anIgE antibody, they are useful as medicines for prevention and treatmentof various allergic immunological diseases, in which IgE participates,for example, asthma, atopic dermatitis, allergic rhinitis, inflammatorybowel diseases and contact dermatitis.

[0040] The diamide compounds (1) or the salts thereof can be formulatedinto various oral and parenteral preparations in the form of a solid,semisolid or liquid by adding a pharmaceutically acceptable carrier inaccordance with a method known per se in the art.

[0041] Examples of the oral preparations include tablets, pills,granules, soft and hard capsules, powders, grains, triturations,emulsions, syrups, pellets and elixirs. Examples of the parenteralpreparations include injections, drops, infusions, ointments, lotions,tonics, sprays, inhalation suspensions, oils, emulsions andsuppositories. The active ingredients according to the present inventionmay be formulated into various preparations in accordance with a methodknown per se in the art. In these preparations, may be used surfactants,excipients, colorants, smell corrigents, preservatives, stabilizers,buffers, suspension stabilizers, isotonic agents and the like, asneeded.

[0042] The dose of the diamide compound (1) or the salt thereof variesaccording to the kind of the compound, the kind of a disease to betreated or prevented, an administration method, the condition, age, sex,weight of a patient to be administered, treatment time, and the like.However, the compound may be administered in a dose of 0.01-1,000 mg/kg(weight)/day. The compound may be administered at once or in severalportions, for example, 2 to 6 portions a day.

EXAMPLES

[0043] The present invention will hereinafter be described in moredetail by the following Examples. However, the present invention is notlimited to these examples. Referential Example 1:

[0044] 5-Phenylpenta-(2E,4E)-dienoic acid⁽¹⁾

[0045] To a solution of 16 ml (72 mmol) of triethyl 4-phosphonocrotonatein anhydrous tetrahydrofuran (100 ml) was added 43 ml (69 mmol) of a 1.6M n-butyllithium solution dropwise with stirring in an ice-salt bathunder nitrogen, and the mixture was stirred for 30 minutes. Then, 5.0 ml(49 mmol) of benzaldehyde was added dropwise to this reaction mixtureover about 5 minutes, and the resultant mixture was stirred for 10minutes in the ice-salt bath and for an additional 3 hours at roomtemperature. A saturated aqueous solution of ammonium chloride was addedto the reaction mixture to conduct extraction with ether. An organiclayer was dried over anhydrous sodium sulfate and then concentratedunder reduced pressure, and the resultant crude oil (15.9 g) waspurified by chromatography on silica gel, thereby obtaining 8.14 g(yield: 82%) of ethyl 5-phenylpenta-(2E,4E)-dienoate.

[0046] Added to a solution of 8.14 g (40.3 mmol) of ethyl5-phenylpenta-(2E,4E)-dienoate synthesized by the above process inmethanol-tetrahydrofuran (40 ml-80 ml) was 40 ml of a 5N aqueoussolution of potassium hydroxide, and the mixture was stirred for 1 hourat room temperature. The reaction mixture was concentrated under reducedpressure, and the resultant residue was cooled in an ice bath. To itwere added 20 ml of chloroform and concentrated hydrochloric acid withvigorous stirring. An aqueous layer and an organic layer were separatedfrom each other, and the aqueous layer was further extracted withchloroform. The resultant organic layers were collected, dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The resultant crude oil was recrystallized from ethyl acetate-hexane topurify it, thereby obtaining 5.91 g (yield: 84%) of the title compound.(1) Saljoughian, M.; Williams, P. G., J. Org. Chem. 1987, 52, 3481-3483.

Example 1

[0047] Preparation of1,4-bis[5-phenylpenta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0048] After 2.49 g (14.3 mmol) of 5-phenylpenta-(2E,4E)-dienoic acidwere added to a solution of 653 mg (6.51 mmol) of homopiperazine inanhydrous dimethylformamide (30 ml), a reaction vessel was transferredto an ice bath, and 2.7 ml (19 mmol) of triethylamine and 3.0 ml (14mmol) of diphenylphosphorylazide were added and the resultant mixturewas stirred for 1 hour. Added to the reaction mixture was 40 ml of a 5%aqueous solution of sodium hydrogencarbonate to conduct extraction withchloroform. An organic layer was dried over anhydrous sodium sulfate andthen concentrated under reduced pressure. The resultant crude oil (8.4g) was purified by column chromatography on alumina and columnchromatography on silica gel, and then recrystallized from ethylacetate-hexane, thereby obtaining 2.18 g (yield: 81%) of the titlecompound as a colorless crystalline powder.

[0049] Melting point: 155-156° C.

[0050]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0051] 1.81(tt,J=6.0,6.0 Hz,2H), 3.58(dd,J=6.0,6.0 Hz,4H),

[0052] 3.70(s,4H), 6.63(d,J=14.6 Hz,2H), 6.90(d,J=15.6 Hz,2H),

[0053] 7.02(dd,J=15.6,10.3 Hz,2H), 7.23(dd,J=14.6,10.3 Hz,2H),

[0054] 7.23-7.37(m,6H), 7.44-7.49(m,4H).

Example 2

[0055] Preparation of1,4-bis[5-(2-methoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0056] In accordance with the same process as in Example 1, 223 mg(yield: 97%) of the title compound was obtained as a colorless amorphouspowder from 200 mg (0.98 mmol) of5-(2-methoxyphenyl)penta-(2E,4E)-dienoic acid and 49 mg (0.49 mmol) ofhomopiperazine.

[0057]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0058] 1.81(tt,J=6.0,6.0 Hz,2H), 3.58(dd,J=6.0,6.0 Hz,4H),

[0059] 3.68(s,4H), 3.83(s,6H), 6.58(d,J=14.5 Hz,2H),

[0060] 6.92(ddd,J=7.4,7.4,1.0 Hz,2H), 6.97-7.13(m,4H),

[0061] 7.00(dd,J=8.4,1.0 Hz,2H),

[0062] 7.23(ddd,J=14.5,9.0,1.5 Hz,2H),

[0063] 7.25(ddd,J=8.4,7.4,1.7 Hz,2H), 7.48(dd,J=7.4,1.7 Hz,2H).

Example 3

[0064] Preparation of1,4-bis[5-(3-trifluoromethylphenyl)-penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0065] In accordance with the same process as in Example 1, 216 mg(yield: 94%) of crude crystals of the title compound were obtained from202 mg (0.84 mmol) of 5-(3-trifluoro-methylphenyl) penta-(2E,4E)-dienoicacid and 42 mg (0.42 mmol) of homopiperazine. The crude crystals thusobtained were recrystallized from chloroform-hexane, thereby obtaining acolorless crystalline powder.

[0066] Melting point: 181-182° C.

[0067]¹H-NMR (CDCl₃) (mixture of amide rotamers) δ:

[0068] 1.90-2.05(m,2H), 3.56-3.88(m,4H), 3.80(s,4H),

[0069] 6.48(br d,J=14.5 Hz,1.3H), 6.50(br d,J=14.5 Hz,0.7H),

[0070] 6.82-7.09(m,4H), 7.40-7.73(m,10H).

Example 4

[0071] Preparation of1,4-bis[5-(3-methoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0072] In accordance with the same process as in Example 1, 133 mg(yield: 62%) of the title compound was obtained as a pale yellowamorphous powder from 186 mg (0.91 mmol) of 5-(3-methoxyphenyl)penta-(2E,4E)-dienoic acid and 46 mg (0.46 mmol) of homopiperazine.

[0073]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0074] 1.81(tt,J=6.0,6.0 Hz,2H), 3.58(dd,J=6.0,6.0 Hz,4H),

[0075] 3.69(s,4H), 3.78(s,6H), 6.63(d,J=14.8 Hz,2H),

[0076] 6.85(ddd,J=8.1,2.6,0.9 Hz,2H), 6.87(d,J=15.1 Hz,2H),

[0077] 7.02(dd,J=15.1,10.5 Hz,2H), 6.99-7.09(m,4H),

[0078] 7.23(dd,J=14.8,10.5 Hz,2H), 7.24(dd,J=8.1,8.1 Hz,2H).

Example 5

[0079] Preparation of1,4-bis[5-(4-fluorophenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0080] In accordance with the same process as in Example 1, 217 mg(yield: 94%) of the title compound was obtained as a colorless amorphouspowder from 202 mg (1.1 mmol) of 5-(4-fluorophenyl)penta-(2E,4E)-dienoic acid and 47 mg (0.47 mmol) of homopiperazine. Theamorphous powder thus obtained was recrystallized frommethanol-chloroform-hexane, thereby obtaining a colorless crystallinepowder.

[0081] Melting point: 230-231° C.

[0082]¹H-NMR (CD₃OD-CDCl₃) (mixture of amide rotamers) δ:

[0083] 1.90-2.05(m,2H), 3.55-3.75(m,4H), 3.78(s,4H),

[0084] 6.43(br d,J=14.5 Hz,1.3H), 6.47(br d,J=14.5 Hz,0.7H),

[0085] 6.82-6.91(m,4H), 7.06(dd,J=8.7,³J_(HF)=8.7 Hz,4H),

[0086] 7.35-7.55(m,6H).

Example 6

[0087] Preparation of1,4-bis[5-(4-trifluoromethylphenyl)-penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0088] In accordance with the same process as in Example 1, 217 mg(yield: 79%) of the title compound was obtained as a colorless amorphouspowder from 242 mg (1.0 mmol) of 5-(4-trifluoromethylphenyl)penta-(2E,4E)-dienoic acid and 51 mg (0.51 mmol) of homopiperazine. Theamorphous powder thus obtained was recrystallized frommethanol-chloroform-hexane, thereby obtaining colorless needles.

[0089] Melting point: 233-235° C.

[0090]¹H-NMR (CDCl₃) (mixture of amide rotamers) δ:

[0091] 2.00(br tt,J=6.1,6.1 Hz,2H), 3.58-3.82(m,8H),

[0092] 6.48(d,J=6.7 Hz,1.3H), 6.52(d,J=6.7 Hz,0.7H),

[0093] 6.84-7.04(m,4H), 7.41-7.64(m,10H).

Example 7

[0094] Preparation of1,4-bis[5-(4-tert-butylphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0095] In accordance with the same process as in Example 1, 410 mg(yield: 78%) of the title compound was obtained as a colorless amorphouspowder from 460 mg (2.0 mmol) of 5-(4-tert-butylphenyl)penta-(2E,4E)-dienoic acid and 100 mg (1.0 mmol) of homopiperazine. Theamorphous powder thus obtained was recrystallized from ethylacetate-hexane, thereby obtaining colorless needles.

[0096] Melting point: 162-164° C.

[0097]¹H-NMR (CDCl₃) (mixture of amide rotamers) δ:

[0098] 1.32(s,18H), 1.90-2.07(m,2H), 3.58-3.82(m,8H),

[0099] 6.39(d,J=14.7 Hz,1.3H), 6.42(d,J=14.7 Hz,0.7H),

[0100] 6.81-6.92(m,4H), 7.29-7.60(m,1OH).

Example 8

[0101] Preparation of1,4-bis[(5-(4-chlorophenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0102] In accordance with the same process as in Example 1, 122 mg(yield: 65%) of the title compound was obtained as a colorlesscrystalline powder from 197 mg (0.94 mmol) of 5-(4-chlorophenyl)penta-(2E,4E)-dienoic acid and 39 mg (0.39 mmol) of homopiperazine.

[0103] Melting point: 248-250° C.

[0104]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0105] 1.80(tt,J=6.0,6.0 Hz,2H), 3.58(dd,J=6.0,6.0 Hz,4H),

[0106] 3.69(s,4H), 6.63(d,J=14.6 Hz,2H),

[0107] 6.88(d,J=15.5 Hz,2H), 7.02(dd,J=15.5,10.4 Hz,2H),

[0108] 7.21(dd,J=14.6,10.4 Hz,2H), 7.35(d,J=8.6 Hz,4H),

[0109] 7.48(d,J=8.6 Hz,4H).

Example 9

[0110] Preparation of1,4-bis[5-(4-di-n-butylaminophenyl)-penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepinedihydrochloride:

[0111] In accordance with the same process as in Example 1, 161 mg(yield: 79%) of1,4-bis[5-(4-di-n-butylaminophenyl)-penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepinewas obtained as a yellow oil from 192 mg (0.64 mmol) of5-(4-di-n-butylaminophenyl) penta-(2E,4E)-dienoic acid and 31 mg (0.31mmol) of homopiperazine. Added to a solution of 130 mg of thethus-obtained yellow oil in ethanol (5 ml) was 0.5 ml of 1N hydrochloricacid, and the resultant mixture was concentrated under reduced pressure.Thereafter, ether was added, thereby obtaining the title compound as ayellow amorphous powder.

[0112]¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:

[0113] 0.91(t,J=7.4 Hz,12H), 1.33(tq,J=7.4,7.4 Hz,8H),

[0114] 1.53(tt,J=7.4,7.4 Hz,8H), 1.80(br tt,J=5.9,5.9 Hz,2H),

[0115] 3.30(t,J=7.4 Hz,8H), 3.56(br dd,J=5.9,5.9 Hz,4H),

[0116] 3.67(s,4H), 6.47(d,J=14.7 Hz,2H), 6.70-6.81(m,4H),

[0117] 6.77(d,J=8.6 Hz,4H), 7.16-7.32(m,2H),

[0118] 7.32(d,J=8.6 Hz,4H).

Example 10

[0119] Preparation of1,4-bis[5-(4-methoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0120] In accordance with the same process as in Example 1, crudecrystals were obtained from 200 mg (0.98 mmol) of 5-(4-methoxyphenyl)penta-(2E,4E)-dienoic acid and 49 mg (0.49 mmol) of homopiperazine. Thethus-obtained crude crystals were recrystallized from chloroform-hexane,thereby obtaining 213 mg (yield: 92%) of the title compound as acolorless crystalline powder.

[0121] Melting point: 210-212° C.

[0122]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0123] 1.80(tt,J=6.0,6.0 Hz,2H), 3.57(dd,J=6.0,6.0 Hz,4H),

[0124] 3.68(s,4H), 3.78(s,6H), 6.55(d,J=14.7 Hz,2H),

[0125] 6.80-6.95(m,4H), 6.90(d,J=8.9 Hz,4H),

[0126] 7.21(ddd,J=14.7,7.5,2.7 Hz,2H), 7.41(d,J=8.9 Hz,4H).

Example 11

[0127] Preparation of1,4-bis[5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0128] In accordance with the same process as in Example 1, 194 mg(quantitative) of the title compound was obtained as a colorlessamorphous powder from 204 mg (0.87 mmol) of 5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoic acid and 37 mg (0.37 mmol) of homopiperazine.

[0129]¹H-NMR (DMSO-d₆, 120° C.) 67 :

[0130] 1.81(tt,J=6.0,6.0 Hz,2H), 3.57(dd,J=6.0,6.0 Hz,4H),

[0131] 3.68(s,4H), 3.83(s,12H), 6.50(d,J=14.2 Hz,2H),

[0132] 6.65(d,J=8.4 Hz,4H), 7.07(d,J=15.3 Hz,2H),

[0133] 7.19(dd,J=14.2,10.6 Hz,2H), 7.20(t,J=8.4 Hz,2H),

[0134] 7.29(dd,J=15.3,10.6 Hz,2H).

Example 12

[0135] Preparation of1,4-bis[5-(2,4-dimethoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0136] In accordance with the same process as in Example 1, 170 mg(yield: 73%) of the title compound was obtained as a colorless amorphouspowder from 206 mg (0.88 mmol) of 5-(2,4-dimethoxyphenyl)penta-(2E,4E)-dienoic acid and 44 mg (0.44 mmol) of homopiperazine.

[0137]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0138] 1.80(tt,J=5.9,5.9 Hz,2H), 3.56(dd,J=5.9,5.9 Hz,4H),

[0139] 3.67(s,4H), 3.79(s,6H), 3.83(s,6H),

[0140] 6.50(d,J=14.6 Hz,2H), 6.52(dd,J=8.5,2.3 Hz,2H),

[0141] 6.56(d,J=2.3 Hz,2H), 6.90(dd,J=15.6,9.8 Hz,2H),

[0142] 7.00(d,J=15.6 Hz,2H), 7.20(dd,J=14.6,9.8 Hz,2H),

[0143] 7.40(d,J=8.5 Hz,2H).

Example 13

[0144] Preparation of1,4-bis[5-(4-tert-butyl-2-methoxy-phenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0145] In accordance with the same process as in Example 1, 238 mg(yield: 91%) of the title compound was obtained as a pale yellowamorphous powder from 234 mg (0.90 mmol) of5-(4-tert-butyl-2-methoxyphenyl) penta-(2E,4E)-dienoic acid and 45 mg(0.45 mmol) of homopiperazine.

[0146]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0147] 1.30(s,18H), 1.80(tt,J=6.0,6.0 Hz,2H),

[0148] 3.57(dd,J=6.0,6.0 Hz,4H), 3.68(s,4H), 3.84(s,6H),

[0149] 6.55(d,J=14.5 Hz,2H), 6.93-7.12(m,8H),

[0150] 7.22(ddd,J=14.5,8.6,1.6 Hz,2H), 7.40(d,J=7.8 Hz,2H).

Example 14

[0151] Preparation of1,4-bis[5-(3,4-dimethoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0152] In accordance with the same process as in Example 1, 182 mg(yield: 83%) of the title compound was obtained as a colorless amorphouspowder from 217 mg (0.82 mmol) of 5-(3,4-dimethoxyphenyl)penta-(2E,4E)-dienoic acid and 41 mg (0.41 mmol) of homopiperazine.

[0153]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0154] 1.81(tt,J=5.8,5.8 Hz,2H), 3.58(dd,J=5.8,5.8 Hz,4H),

[0155] 3.68(s,4H), 3.78(s,6H), 3.80(s,6H),

[0156] 6.55(d,J=14.6 Hz,2H), 6.81(d,J=15.8 Hz,2H),

[0157] 6.91(dd,J=15.8,9.9 Hz,2H), 6.91(d,J=8.4 Hz,2H),

[0158] 7.02(dd,J=8.4,2.1 Hz,2H), 7.10(d,J=2.1 Hz,2H),

[0159] 7.21(dd,J=14.6,9.9 Hz,2H).

Example 15

[0160] Preparation of1,4-bis[5-(3,5-dimethoxyphenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0161] In accordance with the same process as in Example 1, 186 mg(yield: 95%) of the title compound was obtained as a colorless amorphouspowder from 207 mg (0.83 mmol) of 5-(3,5-dimethoxyphenyl)penta-(2E,4E)-dienoic acid and 37 mg (0.37 mmol) of homopiperazine.

[0162]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0163] 1.81(tt,J=6.0,6.0 Hz,2H), 3.58(dd,J=6.0,6.0 Hz,4H),

[0164] 3.68(s,4H), 3.76(s,12H), 6.43(t,J=2.2 Hz,2H),

[0165] 6.63(d,J=14.5 Hz,2H), 6.65(d,J=2.2 Hz,4H),

[0166] 6.82(d,J=15.4 Hz,2H), 7.01(dd,J=15.4,10.7 Hz,2H),

[0167] 7.21(dd,J=14.5,10.7 Hz,2H).

Example 16

[0168] Preparation of1,4-bis[5-(2,4,6-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0169] In accordance with the same process as in Example 1, crudecrystals were obtained from 211 mg (0.80 mmol) of5-(2,4,6-trimethoxyphenyl) penta-(2E,4E)-dienoic acid and 41 mg (0.41mmol) of homopiperazine. The crude crystals were recrystallized fromethanol-ether, thereby obtaining 177 mg (yield: 75%) of the titlecompound as a pale yellow crystalline powder.

[0170] Melting point: 190-195° C.

[0171]¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:

[0172] 1.80(br tt,J=6.0,6.0 Hz,2H),

[0173] 3.56(br dd,J=6.0,6.0 Hz,4H), 3.66(br s,4H), 3.80(s,6H),

[0174] 3.82(s,12H), 6.24(s,4H), 6.36-6.47(m,2H),

[0175] 6.94-7.07(m,2H), 7.10-7.24(m,4H).

Example 17

[0176] Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0177] In accordance with the same process as in Example 1, crudecrystals of 146 mg (quantitative) of the title compound were obtainedfrom 157 mg (0.60 mmol) of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 25 mg (0.25 mmol) of homopiperazine. Thethus-obtained crude crystals were recrystallized from ethanol, therebyobtaining pale yellow needles.

[0178] Melting point: 147-149° C.

[0179]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0180] 1.81(tt,J=6.0,6.0 Hz,2H), 3.58(dd,J=6.0,6.0 Hz,4H),

[0181] 3.69(s,4H), 3.72(s,6H), 3.81(s,12H),

[0182] 6.60(d,J=14.7 Hz,2H), 6.80(s,4H), 6.81(d,J=15.4 Hz,2H),

[0183] 6.97(dd,J=15.4,10.5 Hz,2H), 7.21(dd,J=14.7,10.5 Hz,2H).

Example 18

[0184] Preparation of1,4-bis[5-(3,5-dimethoxy-4-isopropoxy-phenyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0185] In accordance with the same process as in Example 1, 222 mg(yield: 93%) of the title compound was obtained as a colorless amorphouspowder from 220 mg (0.37 mmol) of 5-(3,5-dimethoxy-4-isopropoxyphenyl)penta-(2E,4E)-dienoic acid and 37 mg (0.37 mmol) of homopiperazine.

[0186]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0187] 1.20(d,J=6.2 Hz,12H), 1.81(tt,J=5.9,5.9 Hz,2H),

[0188] 3.58(dd,J=5.9,5.9 Hz,4H), 3.69(s,4H), 3.79(s,12H),

[0189] 4.33(qq,J=6.2,6.2 Hz,2H), 6.59(d,J=14.7 Hz,2H),

[0190] 6.80(s,4H), 6.82(d,J=15.5 Hz,2H),

[0191] 6.97(dd,J=15.5,10.6 Hz,2H), 7.22(dd,J=14.7,10.6 Hz,2H).

Example 19

[0192] Preparation of1,4-bis[5-(2-pyridyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0193] In accordance with the same process as in Example 1, crudecrystals were obtained from 230 mg (1.1 mmol) of 5-(2-pyridyl)penta-(2E,4E)-dienoic acid and 49 mg (0.49 mmol) of homopiperazine. Thecrude crystals were recrystallized from chloroform-ether, therebyobtaining 193 mg (yield: 95%) of the title compound as a colorlesscrystalline powder.

[0194] Melting point: 196-197° C.

[0195]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0196] 1.81(tt,J=6.0,6.0 Hz,2H), 3.59(dd,J=6.0,6.0 Hz,4H),

[0197] 3.70(s,4H), 6.74(d,J=14.6 Hz,2H), 6.93(d,J=15.1 Hz,2H),

[0198] 7.21(ddd,J=7.6,4.8,1.0 Hz,2H),

[0199] 7.25(dd,J=14.6,11.3 Hz,2H), 7.42(dd,J=15.1,11.3 Hz,2H),

[0200] 7.42(br d,J=7.6 Hz,2H), 7.71(ddd,J=7.6,7.6,1.8 Hz,2H),

[0201] 8.52(br d,J=4.8 Hz,2H).

Example 20

[0202] Preparation of1,4-bis[5-(3-pyridyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0203] In accordance with the same process as in Example 1, crudecrystals of 207 mg (yield: 97%) of the title compound were obtained from240 mg (1.1 mmol) of 5-(3-pyridyl)penta-(2E,4E)-dienoic acid and 52 mg(0.52 mmol) of homopiperazine. The thus-obtained crude crystals wererecrystallized from ethanol-ether, thereby obtaining a colorlesscrystalline powder.

[0204] Melting point: 221-222° C.

[0205]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0206] 1.81(tt,J=6.0,6.0 Hz,2H), 3.59(dd,J=6.0,6.0 Hz,4H),

[0207] 3.70(s,4H), 6.67(d,J=13.9 Hz,2H), 6.92(d,J=15.1 Hz,2H),

[0208] 7.12(dd,J=15.1,10.6 Hz,2H), 7.23(dd,J=13.9,10.6 Hz,2H),

[0209] 7.32(dd,J=7.9,4.8 Hz,2H), 7.85(ddd,J=7.9,2.2,1.6 Hz,2H),

[0210] 8.44(dd,J=4.8,1.6 Hz,2H), 8.66(d,J=2.2 Hz,2H).

Example 21

[0211] Preparation of1,4-bis[5-(2-methylthiopyridin-3-yl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0212] In accordance with the same process as in Example 1, crudecrystals of 214 mg (yield: 98%) of the title compound were obtained from191 mg (0.87 mmol) of 5-(2-methylthio-pyridin-3-yl)penta-(2E,4E)-dienoic acid and 43 mg (0.43 mmol) of homopiperazine. Thethus-obtained crude crystals were recrystallized from ethanol-ether,thereby obtaining a colorless crystalline powder.

[0213] Melting point: 182-184° C.

[0214]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0215] 1.80(tt,J=6.0,6.0 Hz,2H), 2.53(s,6H),

[0216] 3.59(dd,J=6.0,6.0 Hz,4H), 3.69(s,4H),

[0217] 6.67(d,J=14.7 Hz,2H), 6.93-7.13(m,4H),

[0218] 7.08(dd,J=7.8,4.6 Hz,2H),

[0219] 7.23(ddd,J=14.7,8.5,1.6 Hz,2H),

[0220] 7.78(dd,J=7.8,1.7 Hz,2H), 8.36(dd,J=4.6,1.7 Hz,2H).

Example 22

[0221] Preparation of 1,4-bis[5-(2,6-dimethoxypyridin-3-yl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0222] In accordance with the same process as in Example 1, crudecrystals of 220 mg (yield: 99%) of the title compound were obtained from194 mg (0.83 mmol) of 5-(2,6-dimethoxy-pyridin-3-yl)penta-(2E,4E)-dienoic acid and 42 mg (0.42 mmol) of homopiperazine. Thethus-obtained crude crystals were recrystallized from chloroform-ether,thereby obtaining a pale yellow crystalline powder.

[0223] Melting point: 227-230° C.

[0224]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0225] 1.79(tt,J=6.0,6.0 Hz,2H), 3.56(dd,J=6.0,6.0 Hz,4H),

[0226] 3.67(s,4H), 3.89(s,6H), 3.96(s,6H),

[0227] 6 .35(d,J=8.1 Hz,2H), 6.51(d,J=14.5 Hz,2H),

[0228] 6.87(br d,J=15.5 Hz,2H), 6.96(dd,J=15.5,9.4 Hz,2H),

[0229] 7.19(ddd,J=14.5,9.4,0.9 Hz,2H), 7.76(d,J=8.1 Hz,2H).

Example 23

[0230] Preparation of1,4-bis[5-(3-quinolyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0231] In accordance with the same process as in Example 1 crudecrystals were obtained from 180 mg (0.84 mmol) of 5-(3-quinolyl)penta-(2E,4E)-dienoic acid and 38 mg (0.38 mmol) of homopiperazine. Thecrude crystals were recrystallized from methanol, thereby obtaining 124mg (yield: 63%) of the title compound as colorless needles.

[0232] Melting point: 222-223° C.

[0233]¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:

[0234] 1.84(tt,J=6.0,6.0 Hz,2H), 3.62(dd,J=6.0,6.0 Hz,4H),

[0235] 3.73(s,4H), 6.67-6.79(m,2H), 7.04-7.16(m,2H),

[0236] 7.24-7.37(m,4H), 7.55(ddd,J=8.3,7.0,1.1 Hz,2H),

[0237] 7.69(ddd,J=8.3,7.0,1.5 Hz,2H), 7.87(br d,J=8.3 Hz,2H),

[0238] 7.96(br d,J=8.3 Hz,2H), 8.31(br d,J=2.0 Hz,2H),

[0239] 9.04(d,J=2.0 Hz,2H).

Example 24

[0240] Preparation of1,4-bis[5-(4-quinolyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0241] In accordance with the same process as in Example 1, 124 mg(yield: 34%) of the title compound was obtained as a pale brownamorphous powder from 347 mg (1.5 mmol) of 5-(4-quinolyl)penta-(2E,4E)-dienoic acid and 70 mg (0.70 mmol) of homopiperazine.

[0242]¹H-NMR (CDCl₃) (mixture of amide rotamers) δ:

[0243] 1.75-2.15(m,2H), 3.60-3.90(m,8H),

[0244] 6.58(d,J=14.7 Hz,1.3H), 6.62(d,J=14.7 Hz,0.7H),

[0245] 7.07-7.22(m,2H), 7.47-7.78(m,10H), 8.00-8.20(m,4H),

[0246] 8.90(d,J=4.4 Hz,1.3H), 8.90(d,J=4.4 Hz,0.7H).

Example 25

[0247] Preparation of1,4-bis[5-(8-quinolyl)penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0248] In accordance with the same process as in Example 1, 248 mg(yield: 69%) of the title compound was obtained as a pale yellowamorphous powder from 330 mg (1.5 mmol) of 5-(8-quinolyl)penta-(2E,4E)-dienoic acid and 70 mg (0.70 mmol) of homopiperazine.

[0249]¹H-NMR (CDCl₃) (mixture of amide rotamers) δ:

[0250] 1.97-2.12(m,2H), 3.58-3.88(m,8H),

[0251] 6.50(br d,J=14.7 Hz,1.5H), 6.53(br d,J=14.7 Hz,0.5H),

[0252] 7.22-7.40(m,2H), 7.44(br dd,J=8.1,4.2 Hz,2H),

[0253] 7.55(br dd,J=7.8,7.8 Hz,2H), 7.61-7.85(m,2H),

[0254] 7.78(br d,J=7.8 Hz,2H), 7.97(br d,J=7.8 Hz,2H),

[0255] 8.08-8.26(m,2H), 8.16(br d,J=8.1 Hz,2H), 8.97(br s,2H).

Example 26

[0256] Preparation of1,4-bis[5-(3-methoxyphenyl)penta-(2E,4E)-dienoyl]piperazine:

[0257] In accordance with the same process as in Example 1, crudecrystals of 304 mg (yield: 94%) of the title compound were obtained from300 mg (1.5 mmol) of 5-(3-methoxy-phenyl)penta-(2E,4E)-dienoic acid and60 mg (0.70 mmol) of piperazine. The thus-obtained crude crystals wererecrystallized from chloroform-ether, thereby obtaining colorlessneedles.

[0258] Melting point: 175-177° C.

[0259]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0260] 3.62(s,8H), 3.79(s,6H), 6.68(d,J=14.6 Hz,2H),

[0261] 6.86(ddd,J=1.2,2.2,8.1 Hz,2H), 6.90(d,J=15.5 Hz,2H),

[0262] 7.03(dd,J=10.3,15.5 Hz,2H), 7.03-7.11(m,4H),

[0263] 7.25(dd,J=10.3,14.6 Hz,2H), 7.26(dd,J=8.1,8.1 HZ,2H).

Example 27

[0264] Preparation of1,4-bis[5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoyl]piperazine:

[0265] In accordance with the same process as in Example 1, crudecrystals were obtained from 172 mg (0.87 mmol) of5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoic acid and 31 mg (0.37 mmol)of piperazine. The crude crystals were recrystallized fromchloroform-ether-hexane, thereby obtaining 145 mg (yield: 77%) of thetitle compound as a colorless crystalline powder.

[0266] Melting point: at least 270° C.

[0267]¹H-NMR (DMSO-d₆, 120° C.) 67 :

[0268] 3.61(s,8H), 3.84(s,12H), 6.55(d,J=14.2 Hz,2H),

[0269] 6.67(d,J=8.4 Hz,4H), 7.10(d,J=15.4 Hz,2H),

[0270] 7.21(t,J=8.4 Hz,2H), 7.22(dd,J=14.2,10.7 Hz,2H),

[0271] 7.31(dd,J=15.4,10.7 Hz,2H).

Example 28

[0272] Preparation of1,4-bis[5-(4-tert-butyl-2-methoxyphenyl)penta-(2E,4E)-dienoyl]piperazine:

[0273] In accordance with the same process as in Example 1, crudecrystals were obtained from 234 mg (0.90 mmol) of5-(4-tert-butyl-2-methoxyphenyl)penta-(2E,4E)-dienoic acid and 39 mg(0.45 mmol) of piperazine. The crude crystals were recrystallized fromethanol-ether, thereby obtaining 171 mg (yield: 66%) of the titlecompound as a colorless crystalline powder.

[0274] Melting point: 200-204° C.

[0275]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0276] 1.30(s,18H), 3.61(s,8H), 3.86(s,6H),

[0277] 6.60(d,J=14.5 Hz,2H), 6.95-7.07(m,8H),

[0278] 7.25(ddd,J=14.5,9.2,1.0 Hz,2H), 7.42(d,J=9.2 Hz,2H).

Example 29

[0279] Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]piperazine:

[0280] In accordance with the same process as in Example 1, crudecrystals of 141 mg (yield: 80%) of the title compound were obtained from161 mg (0.61 mmol) of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoicacid and 37 mg (0.43 mmol) of piperazine. The thus-obtained crudecrystals were recrystallized from methanol-ether-chloroform, therebyobtaining pale yellow needles.

[0281] Melting point: 207-210° C.

[0282]¹H-NMR (CDCl₃) (mixture of amide rotamers) δ:

[0283] 3.55-3.85(m,8H), 3.87(s,6H), 3.90(s,12H),

[0284] 6.46(d,J=14.4 Hz,2H), 6.69(s,4H), 6.75-6.95(m,4H),

[0285] 7.49(br dd,J=14.4,6.2 Hz,1H),

[0286] 7.51(br dd,J=14.4,6.2 Hz,1H).

Example 30

[0287] Preparation of1,4-bis[5-(3,5-dimethoxy-4-isopropoxy-phenyl)penta-(2E,4E)-dienoyl]piperazine:

[0288] In accordance with the same process as in Example 1, crudecrystals were obtained from 193 mg (0.66 mmol) of5-(3,5-dimethoxy-4-isopropoxyphenyl)penta-(2E,4E)-dienoic acid and 29 mg(0.33 mmol) of piperazine. The crude crystals were recrystallized fromethanol-ether-hexane, thereby obtaining 167 mg (yield: 81%) of the titlecompound as colorless flakes.

[0289] Melting point: 196-199° C.

[0290]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0291] 1.20(d,J=6.1 Hz,12H), 3.62(s,8H), 3.80(s,12H),

[0292] 4.33(qq,J=6.1,6.1 Hz,2H), 6.64(d,J=14.7 Hz,2H),

[0293] 6.81(s,4H), 6.84(d,J=15.4 Hz,2H),

[0294] 6.97(dd,J=15.4,10.3 Hz,2H), 7.25(dd,J=14.7,10.3 Hz,2H).

Example 31

[0295] Preparation of1,4-bis[5-(4-quinolyl)penta-(2E,4E)-dienoyl]piperazine:

[0296] In accordance with the same process as in Example 1, 171 mg(yield: 48%) of the title compound were obtained as colorless amorphouspowder from 331 mg (1.5 mmol) of 5-(4-quinolyl)penta-(2E,4E)-dienoicacid and 60 mg (0.70 mmol) of piperazine.

[0297]¹H-NMR (CDCl₃) δ:

[0298] 3.60-3.92(m,8H), 6.60(d,J=14.6 Hz,2H),

[0299] 7.15(dd,J=15.4,10.7 Hz,2H), 7.54(d,J=4.6 Hz,2H),

[0300] 7.58-7.69(m,4H), 7.65(br dd,J=7.1,7.1 Hz,2H),

[0301] 7.76(ddd,J=8.5,7.1,1.5 Hz,2H), 8.13(dd,J=7.1,1.5 Hz,2H),

[0302] 8.14(dd,J=8.5,1.5 Hz,2H), 8.91(d,J=4.6 Hz,2H).

Example 32

[0303] Preparation of1,4-bis[5-(8-quinolyl)penta-(2E,4E)-dienoyl]piperazine:

[0304] In accordance with the same process as in Example 1, 168 mg(yield: 56%) of the title compound was obtained as a pale yellowamorphous powder from 284 mg (1.3 mmol) of5-(8-quinolyl)penta-(2E,4E)-dienoic acid and 53 mg (0.60 mmol) ofpiperazine.

[0305]¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:

[0306] 3.68(m,8H), 6.67-6.84(m,2H), 7.34-7.52(m,4H),

[0307] 7.53(dd,J=8.3,4.2 Hz,2H), 7.60(dd,J=8.1,7.5 Hz,2H),

[0308] 7.90(d,J=8.1 Hz,2H), 7.93-8.16(m,2H),

[0309] 8.04(d,J=7.5 Hz,2H), 8.32(dd,J=8.3,1.9 Hz,2H),

[0310] 8.95(dd,J=4.2,1.9 Hz,2H).

Example 33

[0311] Preparation of ethyl1,4-bis[5-(3,4,5-trimethoxy-phenyl)penta-(2E,4E)-dienoyl]piperazine-2-carboxylate:

[0312] A suspension of 231 mg (1.0 mmol) of ethylpiperazine-2-carboxylate dihydrochloride⁽¹⁾ in anhydrousdimethylformamide (4 ml) was cooled in an ice bath. To the suspensionwere added 0.84 ml (6.0 mmol) of triethylamine, 582 mg (2.2 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid, and 0.33 ml (2.2mmol) of diethyl phosphorocyanidate. The ice bath was removed, and themixture was stirred for 1 hour at room temperature. Added to thereaction mixture were 4 ml of a 5% aqueous solution of sodiumhydrogencarbonate to conduct extraction with chloroform. An organiclayer was dried over anhydrous sodium sulfate, and then concentratedunder reduced pressure. The resultant crude oil (600 mg) was purified bycolumn chromatography on alumina and column chromatography on silica gelto obtain 511 mg (yield: 79%) of the title compound as a pale yellowamorphous powder.

[0313] (1) Jucker, von E.; Rissi, E., Helvetica Chim. Acta, 1962,2383-2402.

[0314]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0315] 1.19(t,J=7.3 Hz,3H), 3.05-3.19(m,1H), 3.25-3.48(m,2H),

[0316] 3.73(s,6H), 3.82(s,12H), 4.04-4.21(m,2H),

[0317] 4.12(q,J=7.3 Hz,2H), 4.54-4.63(m,1H), 5.03-5.08(m,1H),6.61(d,J=14.7 Hz,1H), 6.64(d,J=14.7 Hz,1H), 6.82(s,4H),

[0318] 6.85(d,J=15.6 Hz,1H), 6.87(d,J=15.6 Hz,1H),

[0319] 6.98(dd,J=15.6,10.0 Hz,2H), 7.24(dd,J=14.7,10.0 Hz,1H),

[0320] 7.27(dd,J=14.7,10.0 Hz,1H).

Example 34

[0321] Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]piperazine-2-carboxylicacid:

[0322] Added to a solution of 339 mg (0.52 mmol) of ethyl1,4-bis[5-(3,4,57trimethoxyphenyl)penta-(2E,4E)-dienoyl]piperazine-2-carboxylatesynthesized by the process of Example 33 in methanol-tetrahydrofuran (1ml-1.5 ml) was 0.50 ml (1.5 mmol) of a 3N aqueous solution of potassiumhydroxide, and the mixture was stirred for 1 hour at room temperature. Asaturated saline solution (3 ml) and 1N hydrochloric acid (2 ml) wereadded to the reaction mixture to conduct extraction with chloroform. Anorganic layer was dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resultant crude oil (356 mg)was purified by column chromatography on silica gel to obtain 325 mg(quantitative) of the title compound as a pale yellow amorphous powder.

[0323] The amorphous powder was recrystallized from ethyl acetate-ethylether to obtain a pale yellow crystalline powder.

[0324] Melting point: 212° C. (decomposed).

[0325]¹H-NMR (DMSO-d₆, 120° C.) (no OH proton of the carboxyl group wasobserved) δ:

[0326] 2.98-3.12(m,1H), 3.25-3.42(m,2H), 3.72(s,6H),

[0327] 3.82(s,12H), 4.02-4.23(m,2H), 4.56-4.65(m,1H),

[0328] 4.80-4.90(m,1H), 6.62(d,J=14.7 Hz,1H),

[0329] 6.65(d,J=14.7 Hz,1H), 6.82(s,2H), 6.83(s,2H),

[0330] 6.83(d,J=15.4 Hz,1H), 6.84(d,J=15.4 Hz,1H),

[0331] 6.97(dd,J=15.4,10.4 Hz,1H), 6.98(dd,J=15.4,10.4 Hz,1H),

[0332] 7.22(dd,J=14.7,10.4 Hz,1H), 7.24(dd,J=14.7,10.4 Hz,1H).

Example 35

[0333] Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-N-methylpiperazine-2-carbohydroxamicacid:

[0334] Added to a solution of 148 mg (0.24 mmol) of1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-piperazine-2-carboxylicacid synthesized by the process of Example 34 in anhydrousdimethylformamide (0.5 ml) was 44.9 mg (0.28 mmol) of1,1′-carbonyldiimidazole. After the mixture was stirred for 15 minutes,24.9 mg (0.30 mmol) of N-methylhydroxyamine hydrochloride and 0.050 ml(0.36 mmol) of triethylamine were added, and the mixture was stirred foran additional 15 minutes. Added to the reaction mixture was 3 ml of 0.5Nhydrochloric acid to conduct extraction with chloroform. An organiclayer was dried over anhydrous sodium sulfate, and then concentratedunder reduced pressure. The resultant crude oil (179 mg) was purified bycolumn chromatography on silica gel to obtain 134.6 mg (yield: 87%) ofthe title compound as pale yellow amorphous powder.

[0335]¹H-NMR (CDCl₃) (mixture of amide rotamers; no OH proton wasobserved) δ:

[0336] 2.85(br s,3H), 3.15-4.05(m,4H), 3.87(s,9H),

[0337] 3.91(s,9H), 4.40-4.85(m,2H), 5.35-5.60(m,1H),

[0338] 6.35-6.60(m,2H), 6.69(s,4H), 6.65-6.95(m,4H),

[0339] 7.40-7.60(m,2H).

Referential Example 2

[0340] Preparation of 2-(N,N-dimethylaminomethyl)piperazinetrihydrochloride ⁽²⁾:

[0341] A solution of 5.2 g (17 mmol) of1,4-benzyl-2-hydroxymethyl)piperazine⁽¹⁾ in anhydrous methylene chloride(45 ml) was cooled in an ice bath. To the solution was added 1.6 ml (21mmol) of methanesulfonyl chloride with stirring. The ice bath wasremoved, and the mixture was stirred for 13 hours at room temperature.Added to the reaction mixture were 40 ml of a 5% aqueous solution ofsodium hydrogencarbonate to conduct extraction with methylene chloride.An organic layer was dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resultant crude oil (4.7 g) wasdissolved in anhydrous dimethylformamide (15 ml). To the solution wereadded 3.0 g (38 mmol) of dimethylamine hydrochloride, 5.2 g (38 mmol) ofpotassium carbonate, and 6.2 g (38 mmol) of potassium iodide, and theresultant mixture was stirred for 5 hours at 50° C. Water was added tothe reaction mixture to conduct extraction with chloroform. An organiclayer was dried over anhydrous sodium sulfate, and then concentratedunder reduced pressure. The resultant crude oil was purified by columnchromatography on alumina and column chromatography on silica gel toobtain 3.2 g (yield: 67%) of1,4-dibenzyl-2-(N,N-dimethyl-aminomethyl)piperazine as a colorless oil.

[0342] Added to a solution of 3.1 g (10 mmol) of1,4-benzyl-2-(N,N-dimethylaminomethyl)piperazine synthesized by theabove process in methanol (25 ml) were 5 ml (60 mmol) of concentratedhydrochloric acid and 0.50 g of 10% palladium on carbon. The resultantmixture was stirred for 14 hours at 55° C. under hydrogen. To thereaction mixture was added 12 ml of water, and the catalyst was removedby suction filtration through Celite. The filtrate was concentratedunder reduced pressure, thereby obtaining 2.4 g (yield: 99%) of thetitle compound as a colorless crystalline powder.

[0343] Melting point: 265° C. (decomposed).

[0344] (1) Jucker, von E.; Rissi, E., Helvetica Chim. Acta, 1962,2383-2402.

[0345] (2) Miyamoto, T.; Matsumoto, J.; Chiba, K.; Egawa, H.; Shibamori,K.; Minamide, A.; Nishimura, Y.; Okada, H.; Kataoka, M.; Fujita, M.;Hirose, T.; Nakano, J., J. Med. Chem., 1990, 33, 1465-1656.

Example 36

[0346] Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-2-(N,N-dimethylaminomethyl)-piperazinehydrochloride:

[0347] In accordance with the same process as in Example 33, 371 mg(yield: 58%) of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-2-(N,N-dimethylaminomethyl)-piperazinewas obtained as a pale yellow amorphous powder from 528 mg (2.0 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 252 mg (1.0mmol) of 2-(N,N-dimethylaminomethyl)piperazine trihydrochloridesynthesized by the process described in Referential Example 2. Added toa solution of 110 mg (0.17 mmol) of the thus-obtained amorphous powderin ethanol (10 ml) was 0.35 ml (0.35 mmol) of 1N hydrochloric acid, andthe resultant mixture was concentrated under reduced pressure, therebyobtaining the title compound as a pale yellow amorphous powder.

[0348]¹H-NMR (DMSO-d₆, 120° C.) (no N⁺H proton of the ammonium salt wasobserved) δ:

[0349] 2.81(br s,6H), 2.87-3.50(m,5H), 3.72(s,6H),

[0350] 3.82(s,12H), 3.99-4.38(m,3H), 5.01(m,1H),

[0351] 6.74(br d,J=14.7 Hz,2H), 6.83(s,2H), 6.84(s,2H),

[0352] 6.89(br d,J=15.5 Hz,2H), 7.03(dd,J=15.5,10.5 Hz,1H),

[0353] 7.04(dd,J=15.5,10.5 Hz,1H), 7.29(dd,J=14.7,10.5 Hz,1H),

[0354] 7.30(dd,J=14.7,10.5 Hz,1H).

Example 37

[0355] Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-2-(N,N-diisopropylaminomethyl)-piperazinefumarate:

[0356] In accordance with the same process as in Example 33, 108 mg(yield: 57%) of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-2-(N,N-diisopropylaminomethyl)-piperazinewas obtained as a pale yellow amorphous powder from 153 mg (0.58 mmol)of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 85 mg (0.27mmol) of 2-(N,N-di-isopropylaminomethyl)piperazine trihydrochloridesynthesized by the same process as in Referential Example 2. Added to asolution of 88 mg (0.12 mmol) of the thus-obtained amorphous powder inethanol (10 ml) was 15 mg (0.12 mmol) of fumaric acid, and the resultantmixture was concentrated under reduced pressure, thereby obtaining thetitle compound as a pale yellow amorphous powder.

[0357]¹H-NMR (data for free base of the title compound) (DMSO-d₆, 120°C.) δ:

[0358] 0.95(d,J=6.6 Hz,6H), 0.98(d,J=6.6 Hz,6H),

[0359] 2.51-2.56(m,2H), 3.03(qq,J=6.6,6.6 Hz,2H),

[0360] 2.95-3.30(m,3H), 3.72(s,6H), 3.82(s,12H),

[0361] 4.02-4.45(m,4H), 6.65(br d,J=14.7 Hz,2H), 6.81(s,2H),

[0362] 6.82(s,2H), 6.84(d,J=15.5 Hz,1H), 6.85(d,J=15.5 Hz,1H),

[0363] 6.96(dd,J=15.5,10.4 Hz,1H), 7.00(dd,J=15.5,10.4 Hz,1H),

[0364] 7.24(dd,J=14.7,10.4 Hz,1H), 7.26(dd,J=14.7,10.4 Hz,1H).

Example 38

[0365] Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-2-morpholinomethylpiperazinefumarate:

[0366] In accordance with the same process as in Example 33, 234 mg(yield: 62%) of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-2-morpholinomethylpiperazinewas obtained as pale yellow amorphous powder from 325 mg (1.2 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 165 mg (0.55mmol) of 2-morpholinomethyl-piperazine trihydrochloride synthesized bythe same process as in Referential Example 2. Added to a solution of 204mg (0.30 mmol) of the thus-obtained amorphous powder in ethanol (10 ml)was 35 mg (0.30 mmol) of fumaric acid, and the resultant mixture wasconcentrated under reduced pressure, thereby obtaining the titlecompound as a pale yellow amorphous powder.

[0367]¹H-NMR (DMSO-d₆, 120° C.) (neither N⁺H proton of the ammonium saltnor OH proton of the carboxyl group was observed) δ:

[0368] 2.30-2.50(m,6H), 2.95-3.25(m,3H), 3.56-3.66(m,4H),

[0369] 3.79(s,6H), 3.88(s,12H), 4.08-4.65(m,4H),

[0370] 6.68(br d,J=14.4 Hz,2H), 6.69(s,2H), 6.87(s,4H),

[0371] 6.90(d,J=15.5 Hz,1H), 6.90(d,J=15.5 Hz,1H),

[0372] 7.02(dd,J=15.5,10.2 Hz,2H), 7.30(dd,J=14.4,10.2 Hz,1H),

[0373] 7.32(dd,J=14.4,10.2 Hz,1H).

Example 39

[0374] Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-2-(imidazol-1-ylmethyl)piperazinefumarate:

[0375] In accordance with the same process as in Example 33, 74 mg(yield: 30%) of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-2-(imidazol-1-ylmethyl)piperazinewas obtained as a pale yellow amorphous powder from 221 mg (0.83 mmol)of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 105 mg (0.38mmol) of 2-(imidazol-1-ylmethyl)piperazine trihydrochloride synthesizedby the same process as in Referential Example 2. Added to a solution of74 mg (0.11 mmol) of the thus-obtained amorphous powder in ethanol (10ml) was 13 mg (0.11 mmol) of fumaric acid, and the resultant mixture wasconcentrated under reduced pressure, thereby obtaining the titlecompound as a pale yellow amorphous powder.

[0376]¹H-NMR (DMSO-d₆, 120° C.) (neither N⁺H proton of the ammonium saltnor OH proton of the carboxyl group was observed) δ:

[0377] 3.02-3.57(m,5H), 3.74(s,6H), 3.82(s,12H),

[0378] 4.05-4.28(m,3H), 4.64-4.78(m,1H), 6.33-6.48(m,2H),

[0379] 6.60-6.94(m,5H), 6.62(s,2H), 6.80(s,2H), 6.82(s,2H),

[0380] 7.08(t,J=1.0 Hz,1H), 7.11-7.33(m,2H), 7.47-7.53(m,1H).

Example 40

[0381] Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-2-phenylthiomethylpiperazine:

[0382] In accordance with the same process as in Example 33, 270 mg(yield: 56%) of the title compound was obtained as a pale yellowamorphous powder from 489 mg (1.7 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 203 mg (0.69mmol) of 2-phenylthiomethylpiperazine dihydrochloride synthesized by thesame process as in Referential Example 2.

[0383]¹H-NMR (CDCl₃) δ:

[0384]2.97-3.33(m,3H), 3.16(d,J=7.6 Hz,2H), 3.73(s,3H),

[0385] 3.73(s,3H), 3.83(s,6H), 3.84(s,6H), 4.07-4.21(m,2H),

[0386] 4.29-4.44(m,1H), 4.44-4.58(m,1H), 6.43(d,J=14.7 Hz,1H),

[0387] 6.63(d,J=14.7 Hz,1H), 6.74-6.92(m,3H), 6.80(s,2H),

[0388] 6.82(s,2H), 6.97(dd,J=15.5,10.1 Hz,1H),

[0389] 7.16-7.35(m,5H), 7.39-7.46(m,2H).

Example 41

[0390] Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-1,2,3,4-tetrahydroquinoxaline:

[0391] A solution of 185 mg (0.70 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid in anhydrousdimethylformamide-methylene chloride (0.2 ml-2 ml) was cooled in an icebath. To the solution was added 0.10 ml (1.1 mmol) of oxalyl chloridewith stirring. The ice bath was removed, and the mixture was stirred for30 minutes at room temperature. The reaction mixture was concentratedunder reduced pressure to obtain crude crystals of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl chloride.

[0392] A solution of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoylchloride in methylene chloride (3 ml) was added dropwise to a solutionof 45 mg (0.34 mmol) of 1,2,3,4-tetrahydroquinoxaline⁽¹⁾ in pyridine(0.5 ml) over about 5 minutes with stirring in an ice bath. Aftercompletion of the addition, the mixture was stirred for 1 hour and waterwas added to conduct extraction with chloroform. An organic layer wasdried over anhydrous sodium sulfate and then concentrated under reducedpressure. The resultant crude oil (254 mg) was purified by columnchromatography on alumina and column chromatography on silica gel toobtain 91 mg (yield: 43%) of crude crystals of the title compound. Thecrude crystals were recrystallized from chloroform-ether to obtain paleyellow fien needles.

[0393] (1) Bugle, R. C.; Osteryoung, R. A., J. Org. Chem., 1979, 44,1719-1720.

[0394] Melting point: 183-185° C.

[0395]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0396] 3.71(s,6H), 3.80(s,12H), 3.97(s,4H),

[0397] 6.52(d,J=14.9 Hz,2H), 6.80(s,4H), 6.85-7.00(m,4H),

[0398] 7.21-7.28(m,2H), 7.36(ddd,J=14.9,9.0,1.1 Hz,2H),

[0399] 7.38-7.45(m,2H).

Example 42

[0400] Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-pyrido[2,3-b]-1,2,3,4-tetrahydropyrazine:

[0401] In accordance with the same process as in Example 41, 190 mg(yield: 40%) of crude crystals of the title compound were obtained from477 mg (1.8 mmol) of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoicacid and 102 mg (0.75 mmol) ofpyrido[2,3-b]-1,2,3,4-tetrahydropyrazine⁽¹⁾. The crude crystals wererecrystallized from ethanol to obtain pale yellow fine needles.

[0402] (1) Bugle, R. C.; Osteryoung, R. A., J. Org. Chem, 1979, 44,1719-1720.

[0403] Melting point: 183-185° C.

[0404]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0405]3.72(s,3H), 3.73(s,3H), 3.81(s,6H), 3.81(s,6H),

[0406] 4.00(s,4H), 6.58(d,J=14.7 Hz,1H), 6.83(s,2H),

[0407] 6.83(s,2H), 6.88-7.05(m,5H), 7.21(dd,J=8.1,4.8 Hz,1H),

[0408] 7.35(ddd,J=14.7,8.9,1.1 Hz,1H),

[0409] 7.39(ddd,J=14.7,8.9,1.1 Hz,1H),

[0410] 8.02(dd,J=8.1,1.7 Hz,1H), 8.19(dd,J=4.8,1.7 Hz,1H).

Referential Example 3

[0411] Preparation of 6-(N,N-dimethylamino)hexahydro-1,4-diazepinetrihydrobromide:

[0412] To a solution of 0.53 ml (6.1 mmol) of oxalyl chloride inanhydrous tetrahydrofuran (15 ml) at −78° C. under nitrogen was addeddropwise a solution of 0.50 ml (7.0 mmol) of anhydrous dimethylsulfoxide in anhydrous tetrahydrofuran (2 ml). After 10 minutes, asolution of 2.0 g (4.7 mmol) of1,4-bis(p-toluenesulfonyl)-6-hydroxy-hexahydro-1,4-diazepine⁽¹⁾ inanhydrous dimethyl sulfoxide-tetrahydrofuran (2 ml-5 ml) was addeddropwise. After 20 minutes at −78° C., 1.3 ml (9.3 mmol) oftriethylamine was added dropwise. The cooling bath was removed, and themixture was stirred for 45 minutes at room temperature. Water (3 ml) anda saturated saline solution (3 ml) were added to the reaction mixture toconduct extraction with ether. An organic layer was dried over anhydroussodium sulfate and then concentrated under reduced pressure, and theresultant crude oil was purified by chromatography on silica gel,thereby obtaining 1.0 g (yield: 52%) of1,4-bis(p-toluenesulfonyl)-6-oxohexahydro-1,4-diazepine as a colorlessoil.

[0413] Addition of 102 mg (1.8 mmol) of potassium hydroxide to asolution of 479 mg (5.9 mmol) of dimethylamine hydrochloride in methanol(4 ml) gave a clear solution. To this solution were added 979 mg (2.3mmol) of 1,4-bis(p-toluenesulfonyl)-6-oxohexahydro-1,4-diazepinesynthesized by the above process in methanol (30 ml) and 116 mg (1.8mmol) of sodium cyanoborohydride. After the resultant mixture wasstirred for 15 hours at room temperature, 104 mg (1.7 mmol) ofadditional sodium cyanoborohydride was added, and the mixture wasstirred for an additional 25 hours. A 1N aqueous solution (5 ml) ofsodium hydroxide was added to the reaction mixture, and the mixture wasconcentrated under reduced pressure, followed by extraction withchloroform. An organic layer was dried over anhydrous sodium sulfate andthen concentrated under reduced pressure. The resultant crude oil waspurified by column chromatography on silica gel to obtain 519 mg (yield:50%) of1,4-bis(p-toluenesulfonyl)-6-(N,N-dimethylamino)-hexahydro-1,4-diazepineas a colorless oil.

[0414] Weighed out to a reaction vessel was 250 mg (0.56 mmol) of1,4-bis(p-toluenesulfonyl)-6-(N,N-dimethylamino)-hexahydro-1,4-diazepinesynthesized by the above process, and 0.20 ml (2.3 mmol) of phenol and a30% acetic acid solution (4 ml) of hydrobromic acid were added, followedby stirring for 6 hours in a bath controlled to 70° C. After thereaction mixture was concentrated under reduced pressure, diethyl ether(5 ml) was added to the residue with stirring, and a supernatant wasremoved. This process was repeated twice to remove diethyl ether-solublematerial. The residue was concentrated again under reduced pressure tocompletely remove diethyl ether. Ethanol (2 ml) was added to theresultant residue, and the mixture was stirred for 30 minutes. Diethylether (2 ml) was added to the resultant solution, and the mixture wascooled in an ice bath, thereby obtaining 194 mg (yield: 91%) of thetitle compound as a colorless crystalline powder (melting point: 245°C., decomposed).

[0415] (1) Saari. W. S.; Raab, A. W.; King, S. W., J. Org. Chem., 1971,36, 1711-1714.

Example 43

[0416] Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-6-(N,N-dimethylamino)hexahydro-1,4-diazepinehydrochloride:

[0417] In accordance with the same process as in Example 33, 255 mg(quantitative) of1,4-bis[5-(3,4,5-trimethoxy-phenyl)penta-(2E,4E)-dienoyl]-6-(N,N-dimethylamino)-hexahydro-1,4-diazepinewere obtained as a colorless amorphous powder from 254 mg (0.96 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 155 mg (0.40mmol) of 6-(N,N-dimethylamino)hexahydro-1,4-diazepine trihydrobromidesynthesized by the process described in Referential Example 3. Added toa solution of 104 mg (0.16 mmol) of the resultant amorphous powder inethanol (4 ml) was 0.30 ml (0.30 mmol) of 1N hydrochloric acid, and themixture was concentrated under reduced pressure, thereby obtaining thetitle compound as a yellow amorphous powder.

[0418] H-NMR (DMSO-d₆, 120° C.) δ:

[0419]2.85(s,6H), 3.38-3.63(m,5H), 3.72(s,6H), 3.80(s,12H),

[0420] 3.90-4.09(m,2H), 4.12-4.24(m,2H), 6.70(d,J=14.7 Hz,2H),

[0421] 6.80(s,4H), 6.86(d,J=15.6 Hz,2H),

[0422] 6.99(dd,J=15.6,10.4 Hz,2H), 7.26(dd,J=14.7,10.4 Hz,2H).

Example 44

[0423] Preparation of1,4-bis[5-(2,3,4-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0424] In accordance with the same process as in Example 41, 269 mg(yield: 86%) of crude crystals of the title compound were obtained from308 mg (1.2 mmol) of 5-(2,3,4-trimethoxyphenyl)penta-(2E,4E)-dienoicacid and 53 mg (0.53 mmol) of homopiperazine. The crude crystals wererecrystallized from ethyl acetate-hexane, thereby obtaining a paleyellow crystalline powder.

[0425] Melting point: 172-175° C.

[0426]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0427]1.83(tt,J=5.9,5.9 Hz,2H), 3.57(dd,J=5.9,5.9 Hz,4H),

[0428] 3.75-3.85(m,4H), 3.78(s,6H), 3.80(s,6H), 3.82(s,6H),

[0429] 6.55(d,J=15.3 Hz,2H), 6.77(d,J=8.8 Hz,2H),

[0430] 6.86-7.12(m,4H), 7.15-7.28(m,2H), 7.22(d,J=8.8 Hz,2H).

Example 45

[0431] Preparation of1,4-bis[5-(3,4,5-trimethylphenyl)-penta-(2E,4E)-dienoyl]hexahydro-1,4-diazepine:

[0432] In accordance with the same process as in Example 41, 140 mg(yield: 56%) of the title compound was obtained as pale yellow amorphouspowder from 238 mg (1.1 mmol) of5-(3,4,5-trimethylphenyl)penta-(2E,4E)-dienoic acid and 50 mg (0.50mmol) of homopiperazine.

[0433]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0434]1.80(tt,J=5.8,5.8 Hz,2H), 2.12(s,6H), 2.22(s,12H),

[0435] 3.56(dd,J=5.8,5.8 Hz,4H), 3.67(s,4H),

[0436] 6.56(d,J=14.6 Hz,2H), 6.77(d,J=15.6 Hz,2H),

[0437] 6.93(dd,J=15.6,10.5 Hz,2H), 7.09(s,4H),

[0438] 7.20(dd,J=14.6,10.5 Hz,2H).

Example 46

[0439] Preparation of1,4-bis[5-(4-tert-butyl-2-methoxy-phenyl)penta-(2E,4E)-dienoyl]-2-(N,N-dimethylaminomethyl)-piperazinehydrochloride:

[0440] In accordance with the same process as in Example 41, 85 mg(yield: 68%) of1,4-bis[5-(4-tert-butyl-2-methoxy-phenyl)penta-(2E,4E)-dienoyl]-2-(N,N-dimethylaminomethyl)-piperazinewas obtained as a pale yellow amorphous powder from 114 mg (0.44 mmol)of 5-(4-tert-butyl-2-methoxy-phenyl)penta-(2E,4E)-dienoic acid and 50 mg(0.20 mmol) of 2-(N,N-dimethylaminomethyl)piperazine trihydrochloridesynthesized by the process described in Referential Example 2.

[0441] Added to a solution of 85 mg (0.14 mmol) of the thus-obtainedamorphous powder in ethanol (10 ml) was 0.30 ml (0.3 mmol) of 1Nhydrochloric acid, and the resultant mixture was concentrated underreduced pressure, thereby obtaining the title compound as a pale yellowamorphous powder.

[0442]¹H-NMR (data for free base of the title compound) (DMSO-d₆, 120°C.) δ:

[0443]1.30(s,18H), 2.22(s,6H), 2.95-3.20(m,5H), 3.85(s,6H),

[0444] 4.00-4.50(m,4H), 6.59(dd,J=14.5,4.2 Hz,2H),

[0445] 6.85-7.15(m,8H), 7.26(dd,J=14.8,9.7 Hz,2H),

[0446] 7.43(d,J=7.5 Hz,2H).

Example 47

[0447] Preparation of1,4-bis[5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-(N,N-dimethylaminomethyl)piperazinehydrochloride:

[0448] In accordance with the same process as in Example 41, 83 mg(yield: 53%) of1,4-bis[5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-(N,N-dimethylaminomethyl)piperazinewas obtained as a pale yellow amorphous powder from 144 mg (0.62 mmol)of 5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoic acid and 71 mg (0.28mmol) of 2-(N,N-dimethylaminomethyl)-piperazine trihydrochloridesynthesized by the process described in Referential Example 2.

[0449] Added to a solution of 83 mg (0.14 mmol) of the thus-obtainedamorphous powder in ethanol (10 ml) was 0.30 ml (0.3 mmol) of 1Nhydrochloric acid, and the resultant mixture was concentrated underreduced pressure, thereby obtaining the title compound as a pale yellowamorphous powder.

[0450]¹H-NMR (data for free base of the title compound) (DMSO-d₆, 120°C.) δ:

[0451]2.23(s,6H), 2.90-3.25(m,5H), 3.84(s,12H),

[0452] 4.00-4.50(m,4H), 6.54(dd,J=14.0,3.9 Hz,2H),

[0453] 6.67(d,J=8.5 Hz,4H), 7.15-7.35(m,8H).

Example 48

[0454] Preparation ofN-[1,4-bis[5-(3,4,5-trimethoxy-phenyl)penta-(2E,4E)-dienoyl]-2-piperazinylmethyl]-phthalimide(in the formula, NPhth is a phthalimide group):

[0455] In accordance with the same process as in Example 41, 533 mg(yield: 75%) of the title compound was obtained as a pale yellowamorphous powder from 581 mg (2.2 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 334 mg (1.0mmol) of N-(2-piperazinylmethyl)phthalimide dihydrochloride synthesizedby the same process as in Referential Example 2.

[0456]¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:

[0457]2.91-3.55(m,5H), 3.61-3.75(m,6H), 3.75-3.91(m,12H),

[0458] 3.99-4.38(m,3H), 4.72-4.88(m,1H), 6.35-6.51(m,2H),

[0459] 6.52-7.02(m,9H), 7.29(dd,J=14.4,10.1 Hz,1H),

[0460] 7.68-7.82(m,4H).

Example 49

[0461] Preparation of2-aminomethyl-1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]piperazinehydrochloride:

[0462] A solution of 1.3 ml (26 mmol) of hydrazine hydrate in methanol(2 ml) was added to a suspension of 430 mg (0.58 mmol) ofN-[1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-piperazinylmethyl]phthalimidesynthesized by the process described in Example 48 in methanol (8 ml),and the mixture was stirred for 17 hours at room temperature. Thereaction mixture was concentrated under reduced pressure, and theresultant residue was extracted with chloroform. An organic layer waswashed with a saturated aqueous solution of sodium hydrogencarbonate andwater, dried over anhydrous sodium sulfate, and then concentrated underreduced pressure. The resultant crude oil was purified by columnchromatography on silica gel to obtain 232 mg (yield: 65%) of2-aminomethyl-1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]piperazineas a pale yellow amorphous powder.

[0463] Added to a solution of 93 mg (0.15 mmol) of the thus-obtainedamorphous powder in ethanol (10 ml) was 0.30 ml (0.3 mmol) of 1Nhydrochloric acid, and the resultant mixture was concentrated underreduced pressure, thereby obtaining the title compound as a pale yellowamorphous powder.

[0464]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0465] (No N⁺H proton of the ammonium salt was observed)

[0466] 3.03(br d,J=6.8 Hz,2H), 3.16-3.39(m,3H), 3.72(s,6H),

[0467] 3.73(s,12H), 4.01-4.32(m,3H), 4.68-4.81(m,1H),

[0468] 6.70(d,J=14.6 Hz,2H), 6.82(s,4H), 6.86(d,J=14.6 Hz,2H),

[0469] 6.97(dd,J=14.6,10.2 Hz,2H), 7.28(dd,J=14.6,10.2 Hz,2H).

Referential Example 4

[0470] Preparation of2,5-bis-tert-butoxycarbonyl-8-methyl-2,5,8-triazabicyclo[4,3,0]nonane:

[0471] Added to a solution of 792 mg (12 mmol) of potassium hydroxide inwater (38.5 ml) were 1.00 g (6.0 mmol) of pyrazine-2,3-dicarboxylic acidand 300 mg of 10% palladium on carbon, and the mixture was stirred for16 hours at 50° C. under hydrogen. The catalyst was removed from thereaction mixture by suction filtration through Celite. A concentratedhydrochloric acid was added until the pH of the filtrate was 3, and thesolution was concentrated under reduced pressure. Added to a solution ofthe resultant residue in methanol (20 ml) were 2.5 ml (18 mmol) oftriethylamine and 4.0 g (18 mmol) of di-tert-butyl dicarbonate. Afterthe resultant mixture was stirred for 30 minutes at room temperature,the reaction mixture was concentrated under reduced pressure. Chloroformwas added to the resultant residue, and the resultant solution waswashed successively with water, 2N hydrochloric acid, and a saturatedsaline solution. An organic layer was dried over anhydrous sodiumsulfate and then concentrated under reduced pressure, thereby obtaining2.5 g of an oil containing1,4-bis(tert-butoxycarbonyl)-piperazine-2,3-dicarboxylic acid.

[0472] Added to a solution of 2.5 g of the oil in xylene (20 ml) was0.65 ml (5.9 mmol) of benzylamine, and the mixture was stirred andrefluxed for 1 hour with continuous removal of water by a waterseparator. The reaction mixture was concentrated under reduced pressure,and the resultant residue was purified by column chromatography onsilica gel, thereby obtaining 650 mg (yield: 25%) of8-benzyl-2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo[4,3,0]nonane-7,9-dioneas a colorless oil.

[0473] To a solution of 650 mg (1.5 mmol) of8-benzyl-2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo-[4,3,0]nonane-7,9-dionein tetrahydrofuran (10 ml) was added 4N hydrogen chloride solution inethyl acetate (10 ml) with stirring. After 30 minutes at 50° C., a 2.5Naqueous solution of sodium hydroxide (17 ml) was added to the reactionmixture, and the mixture was extracted with chloroform. An organic layerwas dried over anhydrous sodium sulfate and then concentrated underreduced pressure. The resultant crude oil was purified by columnchromatography on silica gel, thereby obtaining 85 mg (yield: 24%) of8-benzyl-2,5,8-triazabicyclo[4,3,0]nonane-7,9-dione as a colorless oil.

[0474] To a solution of 80 mg (0.33 mmol) of8-benzyl-2,5,8-triazabicyclo[4,3,0]nonane-7,9-dione in diethylene glycoldimethyl ether (1 ml) were added 38 mg (1.0 mmol) of sodium borohydrideand 0.20 ml (1.6 mmol) of a boron trifluoride-diethyl ether complex withstirring for 2 hours at 70° C. under nitrogen. 6N Hydrochloric acid(0.53 ml) was added, and the mixture was stirred for 15 minutes a thesame temperature. To the reaction mixture was added 242 mg (5.8 mmol) ofsodium fluoride with stirring. After 30 minutes at 100° C., a 5N aqueoussolution of sodium hydroxide (0.5 ml) was added, and the mixture wasconcentrated under reduced pressure. The resultant residue was extractedwith diethyl ether, and an organic layer was dried over anhydrous sodiumsulfate and then concentrated under reduced pressure, thereby obtaining19 mg of a crude oil containing8-benzyl-2,5,8-triazabicyclo-[4,3,0]nonane.

[0475] Added to a solution of 19 mg of this oil in tetrahydrofuran (1ml) were 0.030 ml (0.22 mmol) of triethylamine and 44 mg (0.20 mmol) ofdi-tert-butyl dicarbonate. After the resultant mixture was stirred for30 minutes at room temperature, the reaction mixture was concentratedunder reduced pressure. The resultant residue was purified bypreparative thin-layer chromatography on silica gel, thereby obtaining39 mg (yield: 25%) of8-benzyl-2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo-[4,3,0]nonaneas a colorless oil.

[0476] To a solution of 39 mg (0.093 mmol) of8-benzyl-2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo-[4,3,0]nonanesynthesized by the above process in methanol (1.5 ml) were added 40 mg(0.63 mmol) of ammonium formate and 40 mg of 10% palladium on carbon.The mixture was stirred for 1 hour at 70° C. under nitrogen, and thecatalyst was removed from the reaction mixture by suction filtrationthrough Celite. The filtrate was concentrated under reduced pressure,and the resultant crude oil was purified by column chromatography onsilica gel, thereby obtaining 29 mg (yield: 95%) of2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo[4,3,0]nonane as acolorless oil.

[0477] Added to a solution of 29 mg of the thus obtained2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo[4,3,0]-nonane inacetonitrile (0.7 ml) were 0.038 ml (0.51 mmol) of a 37% aqueoussolution of formaldehyde and 9.4 mg (0.15 mmol) of sodiumcyanoborohydride. After the mixture was stirred for 1 hour and 20minutes at room temperature, acetic acid was added until the reactionmixture reached pH 4, and the resultant mixture was stirred for 30minutes at room temperature. The reaction mixture was concentrated underreduced pressure, and the resultant crude oil was purified by columnchromatography on silica gel, thereby obtaining 29 mg (yield: 96%) ofthe title compound as a colorless oil.

Example 50

[0478] Preparation of2,5-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-8-methyl-2,5,8-triazabicyclo[4,3,0]-nonanehydrochloride:

[0479] To a solution of 29 mg (0.085 mmol) of2,5-bis-tert-butoxycarbonyl-8-methyl-2,5,8-triazabicyclo[4,3,0]nonanesynthesized by the process described in Referential Example 4 intetrahydrofuran (1 ml) was added 4N hydrogen chloride solution in ethylacetate (1 ml) with stirring. After 30 minutes at room temperature, andanother 30 minutes at 50° C., the reaction mixture was concentratedunder reduced pressure, thereby obtaining 21 mg of an oil containing8-methyl-2,5,8-triaza-bicyclo[4,3,0]nonane.

[0480] In accordance with the same process as in Example 41, 30 mg(yield: 56%) of2,5-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-8-methyl-2,5,8-triazabicyclo[4,3,0]-nonanewere obtained as a pale yellow amorphous powder from 21 mg of this oiland 58 mg (0.22 mmol) of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoicacid.

[0481] Added to a solution of 30 mg (0.047 mmol) of the thus-obtainedamorphous powder in ethanol (10 ml) was 0.10 ml (0.10 mmol) of 1Nhydrochloric acid, and the resultant mixture was concentrated underreduced pressure, thereby obtaining the title compound as a pale yellowamorphous powder.

[0482]¹H-NMR (data for free base of the title compound) (DMSO-d₆, 120°C.) δ:

[0483] 2.28(s,3H), 2.55-2.64(m,2H), 3.20-3.30(m,2H),

[0484] 3.50-3.67(m,4H), 3.72(s,6H), 3.82(s,12H),

[0485] 4.80-4.88(m,2H), 6.61(d,J=14.7 Hz,2H), 6.81(s,4H),

[0486] 6.84(d,J=15.5 Hz,2H), 6.97(dd,J=15.5,10.4 Hz,2H),

[0487] 7.27(dd,J=14.7,10.4 Hz,2H).

Example 51

[0488] Preparation of4,8-bis[5-(3,4-dimethoxyphenyl)penta-(2E,4E)-dienoyl]-1,4,8-triazabicyclo[4,4,0]decanehydrochloride:

[0489] In accordance with the same process as in Example 41, 117 mg(yield: 72%) of4,8-bis[5-(3,4-dimethoxyphenyl)-penta-(2E,4E)-dienoyl]-1,4,8-triazabicyclo[4,4,0]decanewas obtained as a pale yellow amorphous powder from 146 mg (0.62 mmol)of 5-(3,4-dimethoxyphenyl)penta-(2E,4E)-dienoic acid and 40 mg (0.28mmol) of 1,4,8-triazabicyclo[4,4,0]-decane⁽¹⁾.

[0490] Added to a solution of 117 mg (0.20 mmol) of the thus-obtainedamorphous powder in ethanol (10 ml) was 0.40 ml (0.40 mmol) of 1Nhydrochloric acid, and the resultant mixture was concentrated underreduced pressure to obtain crude crystals of the title compound. Thecrude crystals were recrystallized from methanol-diethyl ether, therebyobtaining a pale yellow crystalline powder.

[0491] (1) Gubert, S; Braojos, C; Sacristan, A; Ortiz, J. A., Synthesis,1991, 318-320.

[0492] Melting point: 220° C. (decomposed).

[0493]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0494]1.92(br dd,J=10.5,10.5 Hz,1H),

[0495] 2.10(ddd,J=12.0,12.0,3.0 Hz,2H), 2.60-2.70(m,2H),

[0496] 2.75-2.90(m,2H), 2.95-3.10(m,2H), 3.79(s,6H),

[0497] 3.81(s,6H), 4.21(br d,J=10.5 Hz,4H),

[0498] 6.62(d,J=14.7 Hz,2H), 6.83(br d,J=14.4 Hz,2H),

[0499] 6.91(dd,J=14.4,8.7 Hz,2H), 6.93(d,J=8.3 Hz,2H),

[0500] 7.04(dd,J=8.3,2.0 Hz,2H), 7.11(d,J=2.0 Hz,2H),

[0501] 7.22(ddd,J=14.7,8.7,1.3 Hz,2H).

Example 52

[0502] Preparation of4,8-bis[5-(3,4,5-trimethylphenyl)-penta-(2E,4E)-dienoyl]-1,4,8-triazabicyclo[4,4,0]decanehydrochloride:

[0503] In accordance with the same process as in Example 41, 83 mg(yield: 66%) of4,8-bis[5-(3,4,5-trimethylphenyl)-penta-(2E,4E)-dienoyl]-1,4,8-triazabicyclo[4,4,0]decanewas obtained as a pale yellow amorphous powder from 111 mg (0.52 mmol)of 5-(3,4,5-trimethylphenyl)penta-(2E,4E)-dienoic acid and 33 mg (0.23mmol) of 1,4,8-triazabicyclo-[4,4,0]-decane⁽¹⁾.

[0504] Added to a solution of 83 mg (0.15 mmol) of the thus-obtainedamorphous powder in ethanol (10 ml) was 0.30 ml (0.30 mmol) of 1Nhydrochloric acid, and the resultant mixture was concentrated underreduced pressure to obtain crude crystals of the title compound. Thecrude crystals were recrystallized from methanol-diethyl ether, therebyobtaining a pale yellow crystalline powder.

[0505] (1) Gubert, S.; Braojos, C.; Sacristan, A.; Ortiz, J. A.,Synthesis, 1991, 318-320.

[0506] Melting point: 250° C. (decomposed).

[0507]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0508]2.18(s,6H), 2.00-2.25(m,5H), 2.29(s,12H),

[0509] 2.80-2.95(m,4H), 3.90-4.10(m,2H), 4.60-4.70(m,2H),

[0510] 6.40(d,J=14.6 Hz,2H), 6.75-6.90(m,4H), 7.26(s,4H),

[0511] 7.45(dd,J=15.8,10.6 Hz,2H).

Referential Example 5

[0512] Preparation of3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)prop-(2E)-ene:

[0513] In accordance with the same process as in Referential Example 1,1.25 g (65%) of crude crystals of the title compound were obtained from1.60 g (7.4 mmol) of3,4-dihydro-6,7-dimethoxy-2-naphthalenecarbaldehyde⁽¹⁾ and 2.20 g (9.7mmol) of triethyl phosphonoacetate. The crude crystals wasrecrystallized from ethyl acetate, thereby obtaining pale yellow flakes.

[0514] (1) Narasimham, N. S.; Mukhopadhyay, T.; Kusurkar, S. S., IndianJ. Chem., 1981, 20B, 546-548.

[0515] Melting point: 225-227° C.

Example 53

[0516] Preparation of1,4-bis[3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

[0517] In accordance with the same process as in Example 41, 290 mg(yield: 97%) of crude crystals of the title compound were obtained from292 mg (1.1 mmol) of3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)prop-(2E)-enoic acid and 51 mg(0.51 mmol) of homopiperazine. The crude crystals were recrystallizedfrom chloroform-hexane, thereby obtaining pale yellow crystallinepowder.

[0518] Melting point: 255° C. (decomposed).

[0519]¹H-NMR (CDCl₃) (mixture of amide rotamers) δ:

[0520] 2.10-2.95(m,2H), 2.43-2.57(m,4H),

[0521] 2.86(br dd,J=8.0,8.0 Hz,4H), 3.60-4.00(m,8H),

[0522] 3.88(s,6H), 3.90(s,6H), 6.28-6.41(m,2H),

[0523] 6.65-6.74(m,6H), 7.47-7.63(m,2H).

Referential Example 6

[0524] Preparation of3-(3,4-dihydro-6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoic acid:

[0525] In accordance with the same process as in Referential Example 1,308 mg (yield: 72%) of crude crystals of the title compound wereobtained from 367 mg (1.5 mmol) of3,4-dihydro-6,7,8-trimethoxy-2-naphthalenecarbaldehyde⁽¹⁾ and 404 mg(1.8 mmol) of triethyl phosphonoacetate. The crude crystals wererecrystallized from ethyl acetate-hexane, thereby obtaining a paleyellow crystalline powder.

[0526] (1) Narasimham, N. S.; Mukhopadhyay, T.; Kusurkar, S. S., IndianJ. Chem., 1981, 20B, 546-548.

[0527] Melting point: 191-194° C.

Example 54

[0528] Preparation of1,4-bis[3-(3,4-dihydro-6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoyllpiperazine:

[0529] In accordance with the same process as in Example 41, 365 mg(quantitative) of crude crystals of the title compound were obtainedfrom 370 mg (1.3 mmol) of3-(3,4-dihydro-6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoic acidsynthesized by the process described in Referential Example 6 and 50 mg(0.58 mmol) of piperazine. The crude crystals were recrystallized fromchloroform-hexane, thereby obtaining a pale yellow crystalline powder.

[0530] Melting point: 241-244° C.

[0531]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0532] 2.48(dd,J=8.0,8.0 Hz,4H), 2.83(dd,J=8.0,8.0 Hz,4H),

[0533] 3.60-3.80(m,8H), 3.86(s,6H), 3.89(s,6H), 3.91(s,6H),

[0534] 6.35(d,J=15.1 Hz,2H), 6.52(s,2H), 7.04(s,2H),

[0535] 7.57(d,J=15.1 Hz,2H).

Referential Example 7

[0536] Preparation of3-(3,4-dihydro-5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoic acid:

[0537] To 612 mg (8.4 mmol) of dimethylformamide was added 0.20 ml (2.1mmol) of phosphorus oxychloride with stirring in an ice bath. The icebath was removed and the reaction mixture was stirred at roomtemperature. After 5 minutes, 460 mg (2.1 mmol) of3,4-dihydro-5,6,7-trimethoxy-naphthalene⁽¹⁾ was added to the resultantsolution, and the resultant mixture was stirred for 10 minutes at 50° C.and for 3 hours at 80° C. A 2N aqueous solution of potassium acetate (6ml) chilled with ice was added to the reaction mixture to conductextraction with diethyl ether. An organic layer was washed with asaturated aqueous solution of sodium hydrogen-carbonate and a saturatedsaline solution, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The resultant crude oil (520 mg)was purified by column chromatography on silica gel, thereby obtaining291 mg (yield: 56%) of3,4-dihydro-5,6,7-trimethoxy-2-naphthalenecarbaldehyde as a colorlessoil.

[0538] In accordance with the same process as in Referential Example 1,173 mg (yield: 99%) of crude crystals of the title compound wereobtained from 150 mg (0.60 mmol) of3,4-dihydro-5,6,7-trimethoxy-2-naphthalenecarbaldehyde synthesized bythe above process and 176 mg (0.79 mmol) of triethyl phosphonoacetate.The crude crystals were recrystallized from ethyl acetate-hexane,thereby obtaining a pale yellow crystalline powder.

[0539] (1) Haworth, R. D.; Moore, B. P.; Pauson, P. L., J. Chem. Soc.,1949, 3271-3278.

[0540] Melting point: 191-193° C.

Example 55

[0541] Preparation of1,4-bis[3-(3,4-dihydro-5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

[0542] In accordance with the same process as in Example 41, 98 mg(yield: 76%) of crude crystals of the title compound were obtained from131 mg (0.45 mmol) of3-(3,4-dihydro-5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoic acidsynthesized by the process described in Referential Example 7 and 20 mg(0.20 mmol) of homopiperazine. The crude crystals were recrystallizedfrom chloroform-hexane, thereby obtaining a pale yellow crystallinepowder.

[0543] Melting point: 176-179° C.

[0544]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0545] 1.80(tt,J=6.0,6.0 Hz,2H), 2.43(dd,J=8.1,8.1 Hz,4H),

[0546] 2.74(dd,J=8.1,8.1 Hz,4H), 3.59(dd,J=6.0,6.0 Hz,4H),

[0547] 3.71(s,4H), 3.75(s,6H), 3.77(s,6H), 3.78(s,6H),

[0548] 6.50(d,J=15.1 Hz,2H), 6.62(s,2H), 6.67(s,2H),

[0549] 7.22(d,J=15.1 Hz,2H).

Referential Example 8

[0550] Preparation of3-(3,4-dihydro-4,4-dimethyl-5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoicacid:

[0551] To anhydrous tetrahydrofuran (10 ml) stirred in an ice bath undernitrogen were added 104 mg (15 mmol) of lithium, 3.9 g (14 mmol) of1-bromo-3-(3,4,5-trimethoxyphenyl)propane⁽¹⁾, and a solution of 0.95 ml(13 mmol) of acetone in tetrahydrofuran (10 ml). After the mixture wasstirred for 17 hours at room temperature, a 2% aqueous solutionof aceticacid (50 ml) chilled with ice was added to conduct extraction withdiethyl ether. An organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and a saturated saline solution,dried over anhydrous sodium sulfate and then concentrated under reducedpressure. The resultant crude oil (4.1 g) was purified by columnchromatography on silica gel, thereby obtaining 860 mg (yield: 24%) of2-methyl-5-(3,4,5-trimethoxyphenyl)pentan-2-ol.

[0552] To 908 mg (3.4 mmol) of2-methyl-5-(3,4,5-trimethoxyphenyl)pentan-2-ol cooled in an ice bath wasadded 5 mg (80 mmol) of 85% sulfuric acid chilled with ice, and themixture was stirred for 30 minutes. Ice water was added to the reactionmixture to conduct extraction with diethyl ether. An organic layer waswashed with a saturated aqueous solution of sodium hydrogencarbonate anda saturated saline solution, dried over anhydrous sodium sulfate andthen concentrated under reduced pressure, thereby obtaining 848 mg of acrude oil containing1,1-dimethyl-1,2,3,4-tetrahydro-6,7,8-trimethoxynaphthalene.

[0553] Added to a solution of 848 mg (about 3.4 mmol) of this oil incarbon tetrachloride (45 ml) were 713 mg (4.0 mmol) ofN-bromosuccinimide and 23 mg (0.095 mmol) of benzoyl peroxide, and themixture was stirred for 3 hours at 85° C. The reaction mixture waswashed with a saturated aqueous solution of sodium hydrogencarbonate anda saturated saline solution, dried over anhydrous sodium sulfate andthen concentrated under reduced pressure. The resultant crude oil waspurified by column chromatography on silica gel, thereby obtaining 430mg (yield: 51%) of3,4-dihydro-4,4-dimethyl-5,6,7-trimethoxy-naphthalene.

[0554] In accordance with the same process as in Referential Example 7,81 mg (yield: 25%) of3,4-dihydro-4,4-dimethyl-5,6,7-trimethoxy-2-naphthalenecarbaldehyde wassynthesized from 294 mg (1.2 mmol) of3,4-dihydro-4,4-dimethyl-5,6,7-trimethoxynaphthalene synthesized by theabove process, and 95 mg (yield: 84%) of crude crystals of the titlecompound were then obtained from 98 mg (0.36 mmol) of3,4-dihydro-4,4-dimethyl-5,6,7-trimethoxy-2-naphthalenecarbaldehyde. Thecrude crystals were recrystallized from diethyl ether-hexane, therebyobtaining pale yellow needles.

[0555] (1) Evans, D. A.; Tannis, S. P.; Hart. D. J., J. Am. Chem. Soc.,1981, 103, 5813-5821.

[0556] Melting point: 178-180° C.

Example 56

[0557] Preparation of1,4-bis[3-(3,4-dihydro-4,4-dimethyl-5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

[0558] In accordance with the same process as in Example 41, 55 mg(yield: 58%) of crude crystals of the title compound were obtained from95 mg (0.29 mmol) of3-(3,4-dihydro-4,4-dimethyl-5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoicacid synthesized by the process described in Referential Example 8 and14 mg (0.14 mmol) of homopiperazine. The crude crystals wererecrystallized from ethyl acetate-hexane, thereby obtaining a paleyellow crystalline powder.

[0559] Melting point: 205-207° C.

[0560]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0561] 1.31(s,12H), 1.85(tt,J=6.0,6.0 Hz,2H), 2.31(s,4H),

[0562] 3.60(dd,J=6.0,6.0 Hz,4H), 3.71(s,4H), 3.77(s,12H),

[0563] 3.79(s,6H), 6.50(d,J=15.1 Hz,2H), 6.62(s,2H),

[0564] 6.63(s,2H), 7.23(d,J=15.1 Hz,2H).

Referential Example 9

[0565] Preparation of 3-(6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoicacid:

[0566] Added to a solution of 100 mg (0.34 mmol) of3-(3,4-dihydro-6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoic acidsynthesized by the process described in Referential Example 6 in toluene(2 ml) was 102 mg (0.41 mmol) of2,3-dichloro-5,6-dicyano-p-benzoquinone, and the mixture was stirred for1 hour and 30 minutes at 100° C. The reaction mixture was concentratedunder reduced pressure, and the resultant crude oil was purified bycolumn chromatography on silica gel, thereby obtaining 88 mg (yield:88%) of crude crystals of the title compound. The crude crystals wererecrystallized from chloroform-hexane, thereby obtaining a pale redcrystalline powder.

[0567] Melting point: 199-201° C.

Example 57

[0568] Preparation of1,4-bis[3-(6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

[0569] In accordance with the same process as in Example 41, 91 mg(yield: 71%) of crude crystals of the title compound were obtained from152 mg (0.53 mmol) of 3-(6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoicacid synthesized by the process described in Referential Example 9 and20 mg (0.20 mmol) of homopiperazine. The crude crystals wererecrystallized from methanol-diethyl ether, thereby obtaining a palebrown crystalline powder.

[0570] Melting point: 199-204° C.

[0571]¹H-NMR (CDCl₃) (mixture of amide rotamers) δ:

[0572] 2.00-2.20(m,2H), 3.70-3.80(m,4H), 3.80-3.90(m,4H),

[0573] 3.98(s,6H), 3.99(s,6H), 4.07(s,3H), 4.08(s,3H),

[0574] 6.92(d,J=15.0 Hz;2H), 6.95(s,2H), 7.60-7.75(m,4H),

[0575] 7.80-8.00(m,2H), 8.14(s,2H).

Referential Example 10

[0576] Preparation of 3-(5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoicacid:

[0577] In accordance with the same process as in Referential Example 9,241 mg (yield: 99%) of crude crystals of the title compound wereobtained from 264 mg (0.85 mmol) of3-(3,4-dihydro-5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoic acidsynthesized by the process described in Referential Example 7. The crudecrystals were recrystallized from chloroform-hexane, thereby obtaining apale red crystalline powder.

[0578] Melting point: 169-170° C.

Example 58

[0579] Preparation of1,4-bis[3-(5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

[0580] In accordance with the same process as in Example 41, 66 mg(yield: 44%) of crude crystals of the title compound were obtained from108 mg (0.37 mmol) of 3-(5,6,7-trimethoxy-2-naphthyl)prop-(2E)-enoicacid synthesized by the process described in Referential Example 10 and17 mg (0.17 mmol) of homopiperazine. The crude crystals wererecrystallized from ethyl acetate-hexane, thereby obtaining a pale browncrystalline powder.

[0581] Melting point: 170-176° C.

[0582]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0583] 1.90(tt,J=6.1,6.1 Hz,2H), 3.69(dd,J=6.1,6.1 Hz,4H),

[0584] 3.82(s,4H), 3.88(s,6H), 3.91(s,6H), 3.96(s,6H),

[0585] 7.10(s,2H), 7.11(d,J=15.3 Hz,2H), 7.56(d,J=15.3 Hz,2H),

[0586] 7.59(dd,J=8.5,1.5 Hz,2H), 7.88(d,J=8.5 Hz,2H),

[0587] 7.89(br s,2H).

Referential Example 11

[0588] Preparation of3-(5,6-dimethoxy-3,3-dimethyl-2-indenyl)prop-(2E)-enoic acid:

[0589] To anhydrous tetrahydrofuran (35 ml) stirred in an ice bath undernitrogen were added 503 mg (70 mmol) of lithium, 7.84 g (32 mmol) of1-bromo-2-(3,4-dimethoxy-phenyl)ethane⁽¹⁾, and a solution of 2.3 ml (32mmol) of acetone in tetrahydrofuran (70 ml). After the mixture wasstirred for 2 hours at room temperature, a 1N aqueous solution of aceticacid (100 ml) chilled with ice was added to conduct extraction withdiethyl ether. An organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and a saturated saline solution,dried over anhydrous sodium sulfate and then concentrated under reducedpressure. The resultant crude oil was purified by column chromatographyon silica gel, thereby obtaining 3.4 g (yield: 47%) of4-(3,4-dimethoxyphenyl)-2-methylbutan-2-ol as a colorless oil.

[0590] To 3.5 g (16 mmol) of 4-(3,4-dimethoxyphenyl)-2-methylbutan-2-olcooled in an ice bath was added 20 ml (320 mmol) of 85% sulfuric acidchilled with ice, and the mixture was stirred for 30 minutes. Ice waterwas then added to the reaction mixture to conduct extraction withdiethyl ether. An organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and a saturated saline solution,dried over anhydrous sodium sulfate and then concentrated under reducedpressure, thereby obtaining 2.6 g of a crude oil containing5,6-dimethoxy-1,1-dimethylindane.

[0591] Added to a solution of 2.6 g (about 13 mmol) of this oil inbenzene (96 ml) were 13.7 g (64 mmol) of pyridinium chlorochromate and31.8 g of Celite, and the mixture was stirred for 1 hour at 85° C.Insoluble materials were removed from the reaction mixture by suctionfiltration through Celite, and the residue on Celite was washed withdiethyl ether and ethyl acetate. The filtrate and washings were combinedand concentrated under reduced pressure. The resultant crude oil waspurified by column chromatography on silica gel, thereby obtaining 2.1 g(yield: 77%) of 5,6-dimethoxy-3,3-dimethylindan-1-one as a colorlessoil.

[0592] Then, 1.1 g (28 mmol) of sodium borohydride were added to asolution of 1.9 g (9.2 mmol) of 5,6-dimethoxy-3,3-dimethylindan-1-one inmethanol (30 ml), and the mixture was stirred for 5 minutes at roomtemperature. After methanol was removed from the reaction mixture byconcentration under reduced pressure, water was added to the residue,and the mixture was extracted with diethyl ether. An organic layer waswashed with a saturated saline solution, dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. Added to asolution of the resultant residue in toluene (50 ml) was 90 mg (0.47mmol) of p-toluenesulfonic acid monohydrate, and the mixture was stirredfor 20 minutes at 120° C. The reaction mixture was concentrated underreduced pressure, and the resultant crude oil was purified by columnchromatography on silica gel to obtain 264 mg (yield: 15%) of5,6-dimethoxy-l,1-dimethylindene as a colorless oil.

[0593] In accordance with the same process as in Referential Example 7,260 mg (yield: 99%) of 5,6-dimethoxy-1,1-dimethyl-2-indenecarbaldehydewas synthesized from 264 mg (1.3 mmol) of5,6-dimethoxy-1,1-dimethylindene synthesized by the above process, and177 mg (yield: 50%) of crude crystals of the title compound were thenobtained from 299 mg (1.3 mmol) of5,6-dimethoxy-1,1-dimethyl-2indenecarbaldehyde. The crude crystals wererecrystallized from diethyl ether-hexane, thereby obtaining a paleyellow crystalline powder.

[0594] (1) Kuhn, H.; Liao, Zeng-Kun, J. Org. Chem., 1982, 47, 2787-2789.

[0595] Melting point: 177-180° C.

Example 59

[0596] Preparation of1,4-bis[3-(5,6-dimethoxy-1,1-dimethyl-2-indenyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

[0597] In accordance with the same process as in Example 41, 69 mg(yield: 66%) of crude crystals of the title compound were obtained from103 mg (0.37 mmol) of3-(5,6-dimethoxy-1,1-dimethyl-2-indenyl)prop-(2E)-enoic acid synthesizedby the process described in Referential Example 11 and 17 mg (0.17 mmol)of homopiperazine. The crude crystals were recrystallized from ethylacetate-hexane, thereby obtaining a pale yellow crystalline powder.

[0598] Melting point: 203-207° C.

[0599]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0600] 1.32(s,12H), 1.85(tt,J=6.0,6.0 Hz,2H),

[0601] 3.64(dd,J=6.0,6.0 Hz,4H), 3.75(s,4H), 3.77(s,6H),

[0602] 3.82(s,6H), 6.63(d,J=15.6 Hz,2H), 6.97(s,2H),

[0603] 6.99(s,2H), 7.04(s,2H), 7.31(d,J=15.6 Hz,2H).

Referential Example 12

[0604] Preparation of3-(1,1-dimethyl-5,6,7-trimethoxy-2-indenyl)prop-(2E)-enoic acid:

[0605] The following conversion was conducted in accordance with thesame process as in Referential Example 8. First, 1.43 g (yield: 46%) of2-methyl-4-(3,4,5-trimethoxyphenyl)-butan-2-ol was synthesized from 3.34g (12 mmol) of 1-bromo-2-(3,4,5-trimethoxyphenyl)-ethane⁽¹⁾. Then, 484mg (yield: 37%) of 1,1-dimethyl-5,6,7-trimethoxyindene was obtained from1.43 g (5.6 mmol) of 2-methyl-4-(3,4,5-trimethoxyphenyl)butan-2-ol, and60 mg (yield: 14%) of 1,1-dimethyl-5,6,7-trimethoxy-2-indenecarbaldehydewere obtained from 379 mg (1.6 mmol) of1,1-dimethyl-5,6,7-trimethoxyindene. Finally, 81 mg (quantitative) ofcrude crystals of the title compound were obtained from 70 mg (0.27mmol) of 1,1-dimethyl-5,6,7-trimethoxy-2-indenecarbaldehyde. The crudecrystals were recrystallized from ethyl acetate-hexane, therebyobtaining a pale yellow crystalline powder.

[0606] (1) Dean, R. T.; Rapport, H., J. Org. Chem., 1978, 43, 2115-2122.

[0607] Melting point: 175-176° C.

Example 60

[0608] Preparation of1,4-bis[3-(1,1-dimethyl-5,6,7-trimethoxy-2-indenyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

[0609] In accordance with the same process as in Example 41, 58 mg(yield: 72%) of crude crystals of the title compound were obtained from80 mg (0.26 mmol) of3-(1,1-dimethyl-5,6,7-trimethoxy-2-indenyl)prop-(2E)-enoic acidsynthesized by the process described in Referential Example 12 and 12 mg(0.12 mmol) of homopiperazine. The crude crystals were recrystallizedfrom ethyl acetate-hexane, thereby obtaining a pale yellow crystallinepowder.

[0610] Melting point: 176-179° C.

[0611]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0612] 1.39(s,12H), 1.83(tt,J=6.1,6.1 Hz,2H),

[0613] 3.63(dd,J=6.1,6.1 Hz,4H), 3.75(s,4H), 3.78(s,6H),

[0614] 3.80(s,6H), 3.90(s,6H), 6.68(d,J=15.6 Hz,2H),

[0615] 6.78(s,2H), 6.94(s,2H), 7.25(d,J=15.6 Hz,2H).

Example 61

[0616] Preparation of4,8-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-1,4,8-triazabicyclo[4,4,0]decanehydrochloride:

[0617] In accordance with the same process as in Example 41,4,8-bis(5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-1,4,8-triazabicyclo[4,4,0]decanewas obtained as a pale yellow amorphous powder from 290 mg (1.1 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 70 mg (0.50mmol) of 1,4,8-triazabicyclo [4,4,0]decane⁽¹⁾. Added to a solution ofthe thus-obtained amorphous powder in ethanol (30 ml) was 0.10 ml (1.2mmol) of concentrated hydrochloric acid, and the resultant mixture wasconcentrated under reduced pressure to obtain crude crystals of thetitle compound. The crude crystals were recrystallized frommethanol-chloroform-diethyl ether, thereby obtaining 199 mg (yield: 60%)of the title compound as a pale yellow crystalline powder.

[0618] (1) Gubert, S.; Braojos, C.; Sacristan, A.; Ortiz, J. A.,Synthesis, 1991, 318-320.

[0619] Melting point: 190° C. (decomposed).

[0620]¹H-NMR (DMSO-d₆, 120° C.) (no N⁺H proton of the ammonium salt wasobserved) δ:

[0621] 2.55-2.85(m,3H), 2.95-3.10(m,2H),

[0622] 3.19(br d,J=8.5 Hz,2H), 3.32(br dd,J=8.5,8.5 Hz,2H),

[0623] 3.73(s,6H), 3.82(s,12H), 4.31(br d,J=13.5 Hz,2H),

[0624] 4.37(br d,J=13.5 Hz,2H), 6.68(d,J=14.6 Hz,2H),

[0625] 6.81(s,4H), 6.87(d,J=15.6 Hz,2H),

[0626] 6.96(dd,J=15.6,10.5 Hz,2H), 7.26(dd,J=14.6,10.5 Hz,2H).

Referential Example 13

[0627] Preparation of ethyl3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)-2-propynoate:

[0628] A solution of 245 mg (1.2 mmol) of 6,7-dimethoxy-2-tetralone inanhydrous tetrahydrofuran (2.0 ml) was added to 2.9 ml (1.5 mmol) of a0.50 M tetrahydrofuran solution of lithium diisopropylamide whilestirring at −78° C. under nitrogen, and the mixture was stirred for 45minutes. Thereafter, a solution of 562 mg (1.6 mmol) ofN-phenyl-trifluoromethanesufonimide in tetrahydrofuran (3.0 ml) wasadded. After stirring the mixture for 15 minutes at −78° C., thereaction vessel was transferred to an ice bath, and stirring wasconducted for 30 minutes. The reaction mixture was concentrated underreduced pressure, and the resultant crude oil was purified by columnchromatography on silica gel to obtain 334 mg (yield: 83%) of3,4-dihydro-6,7-dimethoxy-2-naphthyl-trifluoromethanesulfonate as acolorless oil.

[0629] To a solution of 178 mg (0.53 mmol) of(3,4-dihydro-6,7-dimethoxy-2-naphthyl) trifluoromethane-sulfonate indimethylformamide (2 ml) were added 0.39 ml (3.9 mmol) of ethyl2-propynoate, 84.8 mg (1.0 mmol) of sodium acetate and 14.8 mg (0.020mmol) of bis(triphenylphosphine)-palladium (II) acetate with stirringunder nitrogen, and the mixture was stirred for 1 hour and 30 minutes at60° C. A saturated saline solution was added to the reaction mixture toconduct extraction with benzene-hexane (1:2). An organic layer waswashed with a saturated saline solution, dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The resultantcrude oil was purified by column chromatography on silica gel to obtain76.5 mg (yield: 51%) of crude crystals of the title compound. The crudecrystals were recrystallized from diethyl ether-hexane, therebyobtaining a pale yellow crystalline powder.

[0630] Melting point: 98.5-99.5° C.

Example 62

[0631] Preparation of1,4-bis[3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)-2-propynoyl]hexahydro-1,4-diazepine:

[0632] Added to a solution of 65.2 mg (0.23 mmol) of ethyl3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)-2-propynoate synthesized by theprocess described in Referential Example 13 in methanol-tetrahydrofuran(1:1; 1 ml) was 0.5 ml (2.5 mmol) of a 5N aqueous solution of potassiumhydroxide, and the mixture was stirred for 30 minutes at roomtemperature. A saturated saline solution and 0.25 ml (3.0 mmol) ofconcentrated hydrochloric acid were added to the reaction mixture toconduct extraction with chloroform. An organic layer was dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The resultant concentrated residue was purified by column chromatographyon silica gel to obtain 61.4 mg (quantitative) of3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)-2-propynoic acid as a colorlessamorphous powder.

[0633] In accordance with the same process as in Example 33, crudecrystals of the title compound were obtained from 61.4 mg (0.24 mmol) of3-(3,4-dihydro-6,7-dimethoxy-2-naphthyl)-2-propynoic acid synthesized bythe above process and 11.9 mg (0.12 mmol) of homopiperazine. The crudecrystals were recrystallized from chloroform-hexane, thereby obtaining30.5 mg (yield: 44%) of a pale yellow crystalline powder.

[0634] Melting point: 246-247° C.

[0635]¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:

[0636] 1.60-2.05(m,1H), 2.35-2.55(m,4H), 2.70-2.90(m,4H),

[0637] 3.50-4.00(m,20H), 6.69(br s,2H), 6.79(br s,2H),

[0638] 6.96(br s,2H).

Example 63

[0639] Preparation of1,4-bis[3-(2-naphthyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

[0640] In accordance with the same process as in Example 33, crudecrystals of the title compound were obtained from 224 mg (1.1 mmol) of3-(2-naphthyl)prop-(2E)-enoic acid and 51.6 mg (0.52 mmol) ofhomopiperazine. The crude crystals were recrystallized fromchloroform-diethyl ether, thereby obtaining 200 mg (yield: 84%) of acolorless crystalline powder.

[0641] Melting point: 200-201° C.

[0642]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0643] 1.90(tt,J=5.9,5.9 Hz,2H), 3.70(dd,J=5.9,5.9 Hz,4H),

[0644] 3.83(s,4H), 7.17(d,J=15.5 Hz,2H), 7.44-7.53(m,4H),

[0645] 7.61(d,J=15.5 Hz,2H), 7.73-7.89(m,8H), 8.03(br s, 2H).

Example 64

[0646] Preparation of1,4-bis[3-(3-quinolyl)prop-(2E)-enoyl]hexahydro-1,4-diazepine:

[0647] In accordance with the same process as in Example 33, crudecrystals of the title compound were obtained from 230 mg (0.98 mmol) of3-(3-quinolyl)prop-(2E)-enoic acid hydrochloride and 39.9 mg (0.40 mmol)of homopiperazine. The crude crystals were recrystallized fromchloroform-diethyl ether, thereby obtaining 177 mg (yield: 96%) of acolorless crystalline powder.

[0648] Melting point: 274-276° C.

[0649]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0650] 1.91(tt,J=6.0,6.0 Hz,2H), 3.72(dd,J=6.0,6.0 Hz,4H),

[0651] 3.85(s,4H), 7.35(d,J=15.6 Hz,2H),

[0652] 7.56(br dd,J=8.0,6.9 Hz,2H), 7.64(br d,J=15.6 Hz,2H),

[0653] 7.71(ddd,J=8.5,6.9,1.5 Hz,2H), 7.88(br d,J=8.0 Hz,2H),

[0654] 7.97(br d,J=8.5 Hz,2H), 8.46(br s,2H),

[0655] 9.15(d,J=2.2 Hz,2H).

Referential Example 14

[0656] Preparation of 3-(3,4,5-trimethoxyphenyl)-2-propynoic acids):

[0657] To a solution of 2.36 g (8.0 mmol) of1-iodo-3,4,5-trimethoxybenzene⁽²⁾ in triethylamine (80 ml) were added1.38 ml (9.6 mmol) of 3,3-diethoxy-1-propane, 56 mg (0.080 mmol) ofbis(triphenylphosphine)palladium (II) chloride and 8.0 mg (0.040 mmol)of cuprous iodide with stirring under nitrogen, and the mixture wasstirred for 3 hours at room temperature. Insoluble materials wereremoved from the reaction mixture by suction filtration through Celite,and the filtrate was concentrated under reduced pressure. The resultantcrude oil was purified by column chromatography on silica gel to obtain2.29 g (yield: 97%) of 1,1-diethoxy-3-(3,4,5-trimethoxyphenyl)-2-propyneas colorless needles (melting point: 62.5-63.0° C.).

[0658] Added to a solution of 2.0 g (6.8 mmol) of1,1-diethoxy-3-(3,4,5-trimethoxyphenyl)-2-propyne in acetonitrile (30ml) was 10 ml (60 mmol) of 6N sulfuric acid, and the mixture was stirredfor 1 hour at room temperature. After the reaction mixture wasconcentrated under reduced pressure to remove acetonitrile, the residuewas extracted with ethyl acetate. An organic layer was washed with asaturated saline solution, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The resultant crude oil waspurified by column chromatography on silica gel to obtain 1.42 g (yield:95%) of crude crystals of 3-(3,4,5-trimethoxyphenyl)-2-propyn-1-al. Thecrude crystals were recrystallized from chloroform-hexane, therebyobtaining colorless needles (melting point: 95.5-96.0° C.).

[0659] To a solution of 480 mg (2.2 mmol) of3-(3,4,5-trimethoxyphenyl)-2-propyn-1-al in tert-butyl alcohol (25 ml)cooled in an ice bath were added 15 ml (15 mmol) of a 1 M aqueoussolution of sodium dihydrogenphosphate and 1.96 g (22 mmol) of sodiumchlorite, and the mixture was stirred for 3 hours. To the reactionmixture was added 2 ml (24 mmol) of concentrated hydrochloric acid andthe mixture was extracted with chloroform. An organic layer was washedwith a 10% aqueous solution of sodium thiosulfate acidified withhydrochloric acid, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The resultant residue wasrecrystallized from diethyl ether-hexane, thereby obtaining 427 mg(yield: 83%) of the title compound as a colorless crystalline powder.

[0660] (1) Klemm, L. H.; Gopinath, K. W.; Karaboyas, G. C.; Capp, G. L.;Lee. D. H., Tetrahedron 1964, 20, 871-876.

[0661] (2) Bacon, R. G. R.; Wright, J. R., J. Chem. Soc. 1969, 1978-1981

Example 65

[0662] Preparation of1,4-bis[3-(3,4,5-trimethoxyphenyl)-2-propynoyl]hexahydro-1,4-diazepine:

[0663] In accordance with the same process as in Example 33, crudecrystals of the title compound were obtained from 80 mg (0.34 mmol) of3-(3,4,5-trimethoxyphenyl)-2-propynoic acid⁽¹⁾ synthesized by theprocess described in Referential Example 14 and 16 mg (0.16 mmol) ofhomopiperazine. The crude crystals were recrystallized fromacetone-diethyl ether, thereby obtaining 41 mg (yield: 48%) of acolorless crystalline powder.

[0664] (1) Klemm, L. H.; Gopinath, K. W.; Karaboyas, G. C.; Capp, G. L.;Lee. D. H., Tetrahedron, 1964, 20, 871-876.

[0665] Melting point: 197-198° C.

[0666]¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:

[0667] 1.72-2.12(m,2H), 1.98-2.08(m,4H), 3.55-4.07(m,4H),

[0668] 3.67-3.90(m,18H), 6.66-6.92(m,4H).

Example 66

[0669] Preparation of4,8-bis[3-(3,4,5-trimethoxyphenyl)-2-propynoyl]-1,4,8-triazabicyclo[4,4,0]decane:

[0670] In accordance with the same process as in Example 33, crudecrystals of the title compound were obtained from 80 mg (0.34 mmol) of3-(3,4,5-trimethoxyphenyl)-2-propynoic acid⁽¹⁾ synthesized by theprocess described in Referential Example 14 and 23 mg (0.16 mmol) of1,4,8-triazabicyclo-[4,4,0]decane⁽²⁾. The crude crystals wererecrystallized from acetone-diethyl ether, thereby obtaining 36 mg(yield: 39%) of a colorless crystalline powder.

[0671] (1) Klemm, L. H.; Gopinath, K. W.; Karaboyas, G. C.; Capp, G. L.;Lee. D. H., Tetrahedron, 1964, 20, 871-876.

[0672] (2) Gubert, S.; Braojos, C.; Sacristan, A.; Ortiz, J. A.Synthesis, 1991, 318-320.

[0673] Melting point: 210-211° C.

[0674]¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:

[0675] 1.98-2.08(m,1H), 2.12-2.26(m,2H), 2.43-2.50(m,2H),

[0676] 2.64-2.80(m,2H), 2.83-2.92(m,2H), 3.72-3.86(m,18H),

[0677] 4.22-4.40(m,4H), 6.78-6.87(m,4H).

Referential Example 15

[0678] Preparation of 5-(3,4,5-trimethoxyphenyl)pent-(2E)-en-4-ynoicacid:

[0679] In accordance with the same process as in Referential Example 1,205 mg (yield: 97%) of crude crystals of the title compound wereobtained from 176 mg (0.80 mmol) of3-(3,4,5-trimethoxyphenyl)-2-propyn-1-al synthesized by the processdescribed in Referential Example 14 and 235 mg (1.1 mmol) of triethylphosphonoacetate. The crude crystals were recrystallized from ethylacetate, thereby obtaining pale yellow needles.

[0680] Melting point: 125° C. (decomposed).

Example 67

[0681] Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-pent-(2E)-en-4-ynoyl]hexahydro-1,4-diazepine:

[0682] In accordance with the same process as in Example 33, crudecrystals of the title compound were obtained from 162 mg (0.61 mmol) of5-(3,4,5-trimethoxyphenyl)pent-(2E)-en-4-ynoic acid synthesized by theprocess described in Referential Example 15 and 30 mg (0.30 mmol) ofhomopiperazine. The crude crystals were recrystallized from ethylacetate-diethyl ether-hexane, thereby obtaining 143 mg (yield: 81%) of apale yellow crystalline powder.

[0683] Melting point: 191-193° C.

[0684]¹H-NMR (CdCl₃, 120° C.) (mixture of amide rotamers) δ:

[0685] 1.94-2.07(m,2H), 3.54-3.82(m,8H), 3.87(s,18H),

[0686] 6.69-6.88(m,6H), 6.95-7.12(m,2H).

Example 68

[0687] Preparation of4,8-bis[5-(3,4,5-trimethoxyphenyl)-pent-(2E)-en-4-ynoyl]-1,4,8-triazabicyclo[4,4,0]decanehydrochloride:

[0688] In accordance with the same process as in Example 33, 77 mg(yield: 61%) of4,8-bis[5-(3,4,5-trimethoxyphenyl)-pent-(2E)-en-4-ynoyl]-1,4,8-triazabicyclo[4,4,0]decanewas obtained as a pale yellow amorphous powder from 110 mg (0.42 mmol)of 5-(3,4,5-trimethoxyphenyl)pent-(2E)-en-4-ynoic acid synthesized bythe process described in Referential Example 15 and 28 mg (0.20 mmol) of1,4,8-triazabicyclo[4,4,0]decane⁽¹⁾.

[0689] Added to a solution of 77 mg (0.12 mmol) of the thus-obtainedamorphous powder in ethanol (10 ml) were 0.25 ml (0.25 mmol) of 1Nhydrochloric acid, and the resultant mixture was concentrated underreduced pressure to obtain crude crystals of the title compound. Thecrude crystals were recrystallized from ethanol-diethyl ether, therebyobtaining a pale yellow crystalline powder.

[0690] (1) Gubert, S.; Braojos, C.; Sacristan, A.; Ortiz, J. A.,Synthesis, 1991, 318-320.

[0691] Melting point: 229-231° C.

[0692]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0693] 2.45-2.65(m,4H), 2.80-3.35(m,8H), 3.74(s,6H),

[0694] 3.79(s,12H), 4.25-4.40(m,1H), 6.77(s,4H),

[0695] 6.83(d,J=15.1 Hz,2H), 7.04(d,J=15.1 Hz,2H).

Referential Example 16

[0696] Preparation of 4-(3,4,5-trimethoxyphenyl)benzoic acid:

[0697] To a solution of 137 mg (0.60 mmol) of ethyl 4-bromobenzoate intoluene (1.4 ml) were added a solution of 152 mg (0.72 mmol) of3,4,5-trimethoxyphenylboronic acid⁽¹⁾ in methanol (0.7 ml), 21 mg (0.018mmol) of tetrakis-(triphenylphosphine)palladium, and 0.70 ml (1.4 mmol)of a 2 M aqueous solution of potassium carbonate with stirring undernitrogen, and the mixture was stirred for 5 hours at 80° C. The reactionmixture was concentrated under reduced pressure, and the residue wasdissolved in methanol (1.0 ml). To the solution was added 1.0 ml (5.0mmol) of a 5N aqueous solution of sodium hydroxide. After stirring for 2hours at 70° C., the reaction mixture was concentrated under reducedpressure to remove methanol, and water was added to the residue toconduct extraction with chloroform. An organic layer was washed with asaturated saline solution, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure, thereby obtaining crude crystals.The crude crystals were recrystallized from chloroform-hexane, therebyobtaining 170 mg (yield: 99%) of the title compound as a colorlesscrystalline powder.

[0698] Melting point: 160-164° C.

[0699] (1) W096/26195.

Example 69

[0700] Preparation of1,4-bis[4-(3,4,5-trimethoxyphenyl)-benzoyl]hexahydro-1,4-diazepine:

[0701] In accordance with the same process as in Example 33, 121 mg(yield: 98%) of crude crystals of the title compound were obtained from121 mg (0.42 mmol) of 4-(3,4,5-trimethoxyphenyl)benzoic acid synthesizedby the process described in Referential Example 16 and 20 mg (0.20 mmol)of homopiperazine. The crude crystals were recrystallized from methylenechloride-hexane, thereby obtaining a colorless crystalline powder.

[0702] Melting point: 205-209° C.

[0703]¹H-NMR (CDCl₃) δ:

[0704] 1.90-2.01(m,2H), 3.40-3.88(m,8H), 3.90(s,6H),

[0705] 3.93(m,12H), 6.77(s,4H), 7.47(br d,J=7.5 Hz,4H),

[0706] 7.60(br d,J=7.5 Hz,4H).

Example 70

[0707] Preparation of4,8-bis[4-(3,4,5-trimethoxyphenyl)-benzoyl]-1,4,8-triazabicyclo[4,4,0]decane:

[0708] In accordance with the same process as in Example 33, 133 mg(yield: 98%) of4,8-bis[4-(3,4,5-trimethoxyphenyl)-benzoyl]-1;4,8-triazabicyclo[4,4,O]decanewere obtained as a colorless amorphous powder from 121 mg (0.42 mmol) of4-(3,4,5-trimethoxyphenyl)benzoic acid synthesized by the processdescribed in Referential Example 16 and 28 mg (0.20 mmol) of1,4,8-triazabicyclo[4,4,0]decane⁽¹⁾.

[0709] Added to a solution of 133 mg (0.20 mmol) of the thus-obtainedamorphous powder in ethanol (10 ml) was 0.40 ml (0.40 mmol) of 1Nhydrochloric acid, and the resultant mixture was concentrated underreduced pressure, thereby obtaining crude crystals of the titlecompound. The crude crystals were recrystallized from ethanol-diethylether, thereby obtaining a colorless crystalline powder.

[0710] (1) Gubert, S.; Braojos, C.; Sacristan, A.; Ortiz, J. A.Synthesis, 1991, 318-320.

[0711] Melting point: 256° C. (decomposed) (colorless powder).

[0712]¹H-NMR (DMSO-d₆, 120° C.) (no N⁺H proton of the ammonium salt wasobserved) δ:

[0713] 2.60-3.25(m,4H), 3.30-3.48(m,1H), 3.75(s,6H),

[0714] 3.85(s,12H), 4.01-4.40(m,8H), 6.92(s,4H),

[0715] 7.47(d,J=8.5 Hz,4H), 7.70(d,J=8.5 Hz,4H).

Example 71

[0716] Preparation of1,4-bis[5-nitro-2-(3,4,5-trimethoxy-phenyl)benzoyl]hexahydro-1,4-diazepine:

[0717] In accordance with the same process as in Example 33, 200 mg(yield: 91%) of crude crystals of the title compound were obtained from210 mg (0.63 mmol) of 5-nitro-2-(3,4,5-trimethoxyphenyl)benzoic acid and30 mg (0.30 mmol) of homopiperazine. The crude crystals wererecrystallized from ethyl acetate-hexane, thereby obtaining pale yellowneedles.

[0718] Melting point: 244-245° C.

[0719]¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:

[0720] 1.30-1.51(m,2H), 3.60-3.80(m,8H), 3.73(br s,6H),

[0721] 3.77(br s,12H), 6.60-6.85(m,4H), 7.51-7.80(m,2H),

[0722] 8.00-8.15(m,2H), 8.15-8.30(m,2H).

Example 72

[0723] Preparation of1,4-bis[4-methoxy-3-(3,4,5-trimethoxy-phenyl)benzoyl]hexahydro-1,4-diazepine:

[0724] In accordance with the same process as in Example 41, 87 mg(yield: 69%) of the title compound was obtained as a colorless amorphouspowder from 126 mg (0.40 mmol) of4-methoxy-3-(3,4,5-trimethoxyphenyl)-benzoic acid and 18 mg (0.18 mmol)of homopiperazine.

[0725]¹H-NMR (CDCl₃) δ:

[0726] 1.90-2.00(m,2H), 3.45-3.65(m,4H), 3.70-3.90(m,4H),

[0727] 3.87(s,12H), 3.89(s,12H), 6.73(s,4H),

[0728] 6.98(d,J=8.7 Hz,2H), 7.37(d,J=8.7 Hz,2H), 7.38(s,2H).

Example 73

[0729] Preparation of1,4-bis[4-methyl-3-(3,4,5-trimethoxy-phenyl)benzoyl]hexahydro-1,4-diazepine:

[0730] In accordance with the same process as in Example 33, 98 mg(yield: 73%) of the title compound was obtained as a colorless amorphouspowder from 127 mg (0.42 mmol) of4-methyl-3-(3,4,5-trimethoxyphenyl)benzoic acid and 20 mg (0.20 mmol) ofhomopiperazine.

[0731]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0732] 1.60-1.80(m,2H), 2.27(s,6H), 3.50-3.65(m,4H),

[0733] 3.71(br s,4H), 3.74(s,6H), 3.77(s,12H), 6.56(s,4H),

[0734] 7.18(dd,J=8.0,1.7 Hz,2H), 7.21(d,J=1.7 Hz,2H),

[0735] 7.27(d,J=8.0 Hz,2H).

Example 74

[0736] Preparation of1,4-bis[4-fluoro-3-(3,4,5-trimethoxy-phenyl)benzoyl]hexahydro-1,4-diazepine:

[0737] In accordance with the same process as in Example 41, 82 mg(yield: 71%) of the title compound was obtained as a colorless amorphouspowder from 115 mg (0.37 mmol) of4-fluoro-3-(3,4,5-trimethoxyphenyl)benzoic acid and 17 mg (0.17 mmol) ofhomopiperazine.

[0738]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0739] 1.70-1.90(m,2H), 3.40-3.70(m,4H), 3.67(s,4H),

[0740] 3.75(s,6H), 3.80(s,12H), 6.81(s,4H),

[0741] 7.26(dd,J=10.7,8.5 Hz,2H),

[0742] 7.37(ddd,J=8.5,5.0,2.2 Hz,2H), 7.49(dd,J=7.6,2.2 Hz,2H).

Example 75

[0743] Preparation of1,4-bis[5-(3,4,5-trimethoxyphenyl)-3-pyridinecarbonyl]hexahydro-1,4-diazepine:

[0744] In accordance with the same process as in Example 33, 103 mg(yield: 80%) of crude crystals of the title compound were obtained from121 mg (0.42 mmol) of 5-(3,4,5-trimethoxyphenyl)-3-pyridinecarboxylicacid and 20 mg (0.20 mmol) of homopiperazine. The crude crystals wererecrystallized from ethanol-hexane, thereby obtaining a colorlesscrystalline powder.

[0745] Melting point: 216-217° C.

[0746]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0747] 1.75-1.90(m,2H), 3.50-3.75(m,8H), 3.75(s,6H),

[0748] 3.87(s,12H), 6.98(s,4H), 7.99(dd,J=2.0,2.0 Hz,2H),

[0749] 8.54(d,J=2.0 Hz,2H), 8.92(d,J=2.0 Hz,2H).

Example 76

[0750] Preparation of1,4-bis[5-amino-2-(3,4,5-trimethoxy-phenyl)benzoyl]hexahydro-1,4-diazepine:

[0751] Added to a solution of 39 mg (0.050 mmol) of1,4-bis[5-nitro-2-(3,4,5-trimethoxy-phenyl)benzoyl]hexahydro-1,4-diazepinesynthesized by the process described in Example 71 in acetic acid-ethylacetate (3:2, 2.5 ml) were 39 mg of 10% palladium on carbon, and themixture was stirred for 2 hours at room temperature under hydrogen. Thecatalyst was removed from the reaction mixture by suction filtrationthrough Celite, and the filtrate was concentrated under reducedpressure. A chloroform solution of the residue was washed with asaturated aqueous solution of sodium hydrogencarbonate and a saturatedsaline solution, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The resultant crude oil waspurified by column chromatography on silica gel to obtain 32 mg (yield:90%) of the title compound as a pale yellow amorphous powder.

[0752]¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:

[0753] 1.60-1.75(m,2H), 3.60-3.75(m,8H), 3.67(br s,6H),

[0754] 3.72(br s,12H), 4.93(br s,4H), 6.35-6.45(m,2H),

[0755] 6.60(br s,4H), 6.60-6.75(m,2H), 7.05-7.15(m,2H).

Test Example 1

[0756] Evaluation of Inhibitory Effect On Production of IgE Antibody

[0757] A spleen was enucleated from a mouse (Balb/C, male, aged 8 weeks)and shredded in 0.3% BSA/HBSS to prepare single cells by means of a200-mesh screen. Further, the single cells were hemolyzed by 0.75%ammonium chloride-17 mM Tris solution to prepare a splenocyte suspension(1×10⁷/ml) using RPMI 1640 medium/25 mM HPES/0.3% BSA. After thesuspension was reacted with a mouse anti-mouse Thy-1.2 monoclonalantivody at 4° C. for 1 hour, the reaction mixture was centrifuged, andthe sediment cells were suspended again (1×10⁷/ml, RPMI/HPES/BAS). Afterthe suspension was then reacted with a low-cytotoxic rabbit complement(product of Cedarlane Co.) at 37° C. for 1 hour, killed cells wereremoved by specific gravity centrifugation using lympholyte M (productof Cedarlane Co.) to obtain a B cell fraction as viably cells.

[0758] after B cells (10⁵/0.2 ml/well) were cultured for a day togetherwith LPS (E. coli 026:B6, product of DIFCO Co.) using a 96-well plate,mouse IL-4 (product of Genzyme Co.) was added to conduct culture furtherfor 7 days.

[0759] Each test agent was added on the first day of the culture, andthe amount of IgE in a culture supernatant was measured by ELISA,thereby calculating out the inhibitory effect of the agent on theproduction of an IgE antibody. The inhibitory activities of the testagents at a concentration of 10⁻⁵ M are shown in Table 1. TABLE 1Inhibitory effect on Test compound (Example No.) production of IgE (%) 1 100 17 100 19 20 25 100 29 100 32 85 34 90 36 100 41 100 42 95

INDUSTRIAL APPLICABILITY

[0760] The novel diamide compounds (1) according to the presentinvention have an excellent inhibitory effect on the production of anIgE antibody and are hence useful as agents for preventing and treatingvarious allergic immunological diseases.

1. A compound represented by the following general formula (1):

wherein A is a phenyl, naphthyl, dihydronaphthyl, indenyl, pyridyl,indolyl, isoindolyl, quinolyl or isoquinolyl group which may besubstituted; B is a group of —CH═CH—, —C≡C—, —(CH═CH)₂—, —CH═CH—C≡C— or—C≡C—CH═CH—, or a divalent residue of benzene, pyridine, pyrimidine orpyrazine, which may be substituted; and W is a formula

in which X is (Y¹, Y² and Y³ are the same or different from one anotherand are independently a hydrogen atom, —COOR¹ (R¹ is a hydrogen atom ora lower alkyl group), —CON(R²)R³ (R² and R³ are the same or differentfrom each other and are independently a hydrogen atom, or a hydroxyl ora lower alkyl group), —CH₂—N(R⁴)R⁵ (R⁴ and R⁵ are the same or differentfrom each other and are independently a hydrogen atom or a lower alkylgroup, or R⁴ and R⁵ may form, together with the adjacent nitrogen atom,a heterocyclic ring which may further have an oxygen, nitrogen or sulfuratom), or —CH₂—S—R⁶ (R⁶ is a lower alkyl, phenyl or pyridyl group), orY¹ and Y² may couple to each other to form an alkylene group which maybe through an oxygen, nitrogen or sulfur atom, Z is a benzene orpyridine ring, and n is an integer of 2 or 3, with the proviso that whenB is a p-phenylene group, and W is a 1,4-piperazinyl group, A is not aphenyl group, and when B is —CH═CH—, A is not a phenyl group which maybe substituted, or a salt thereof, or a hydrate or solvate thereof. 2.The compound according to claim 1, wherein A is a phenyl, naphthyl,dihydronaphthyl, indenyl, pyridyl, indolyl, isoindolyl, quinolyl orisoquinolyl group which may have 1-3 substituents selected from among ahydroxyl group, halogen atoms, lower alkyl groups which may besubstituted by 1-3 halogen atoms, lower alkoxy groups, an amino groupwhich may be substituted by one or two lower alkyl groups, and loweralkylthio groups.
 3. A medicine comprising the compound according toclaim 1 or 2 as an active ingredient.
 4. The medicine according to claim3, which is an agent for inhibiting the production of an IgE antibody.5. The medicine according to claim 3 or 4, which is an agent forpreventing and treating an allergic immunological disease.
 6. Themedicine according to any one of claims 3 to 5, which is an agent forpreventing and treating asthma, atopic dermatitis, allergic rhinitis,inflammatory large bowel disease or contact dermatitis.
 7. A medicinalcomposition comprising the compound according to claim 1 or 2 and apharmaceutically acceptable carrier.
 8. Use of the compound according toclaim 1 or 2 for a medicine.
 9. The use according to claim 8, whereinthe medicine is an agent for inhibiting the production of an IgEantibody.
 10. The use according to claim 8, wherein the medicine is anagent for preventing and treating an allergic immunological disease. 11.The use according to claim 8, wherein the medicine is an agent forpreventing and treating asthma, atopic dermatitis, allergic rhinitis,inflammatory large bowel disease or contact dermatitis.
 12. A method oftreating an allergic immunological disease, which comprisesadministering an effective amount of the compound according to claim 1or
 2. 13. The method according to claim 12, wherein the allergicimmunological disease is asthma, allergic rhinitis, inflammatory largebowel disease or contact dermatitis.